tbuckley/cabot-search huggingface dataset:
IMMU-56. CXCR1/2 MODIFIED CARs CO-OPT RADIATION-INDUCED IL-8 FOR ENHANCED CHEMOTAXIS OF THE CAR T CELLS AND MAXIMAL ANTI-TUMOR EFFICACY
Authors: Linchun Jin, Haipeng Tao, Wang Zhang, Yu Long, Kyle Dyson, Aida Karachi, Loic Deleyrolle, Elias Sayour, Maryam Rahman, Duane Mitchell, Didier Rajon, Changlin Yang, Paul Kubilis, Frank Bova, Zhiguo Lin, Jianping Huang
Journal: Neuro-Oncology (2018)

Glioblastomas (GBM) are heterogeneous brain tumors with capacity for malignant propagation. The treatment options are confined to surgery and chemo/radiation with marginal efficacy, thus, identifying novel markers/targets and development of novel targeted therapeutics is requisite. Cancer immunotherapy provides a unique tumor-specific therapy with exquisite precision; however, very few glioma-specific targets have been discovered. We demonstrated that CD70 is ectopically overexpressed on adult and pediatric gliomas. The expression on glial tumor cells is a markedly poor prognostic marker, mediates the recruitment of immunosuppressive myeloid cells through upregulated chemokine networks in GBM tumor cells, and results in the deletion of CD8+ cytotoxic lymphocytes. As such, this molecule plays an important role in glioma-induced immunosuppression and makes the elimination of CD70+ tumor cells an attractive axis for therapeutic targeting. To address the key obstacle in treating solid tumors using CAR-T cells, we have developed CD70 CAR-2.0 to co-opt the IL-8 chemokine pathway upregulated in CD70+ gliomas by radiation to enhance CNS tropism and persistence in preclinical glioma models. The CD70 CAR-1.0 was respectively linked with IL-8 receptors, CXCR1 and CXCR2 and cloned into a retroviral vector. The CAR-transduced T cells were tested against GBM lines (including primary tumors) in vitro and human GBM xenograft. The CAR-T cell tumor trafficking/persistence, phenotype, and antitumor efficacy were evaluated. Radiation markedly enhanced the secretion of IL-8 by glioma cells. While mice receiving unmodified CD70 CAR-T cells undergo gradual disease progression with anergic/exhausted phenotypes, the IL-8R-modified CAR-T cells illustrate markedly enhanced tumor migration and persistence and induce complete tumor regression and long-lasting immunologic memory. We have co-opted IL-8 release from radiated malignant gliomas, to enhance intra-tumoral T cell trafficking through a new CAR design for maximal anti-tumor activity, thus provide a novel strategy for CAR-T therapy targeting these tumors.
Time-to-event analysis for sports injury research part 1: time-varying exposures
Authors: Rasmus Oestergaard Nielsen, Michael Lejbach Bertelsen, Daniel Ramskov, Merete Møller, Adam Hulme, Daniel Theisen, Caroline F Finch, Lauren Victoria Fortington, Mohammad Ali Mansournia, Erik Thorlund Parner
Journal: British Journal of Sports Medicine (2018)

Background ‘How much change in training load is too much before injury is sustained, among different athletes?’ is a key question in sports medicine and sports science. To address this question the investigator/practitioner must analyse exposure variables that change over time, such as change in training load. Very few studies have included time-varying exposures (eg, training load) and time-varying effect-measure modifiers (eg, previous injury, biomechanics, sleep/stress) when studying sports injury aetiology. Aim To discuss advanced statistical methods suitable for the complex analysis of time-varying exposures such as changes in training load and injury-related outcomes. Content Time-varying exposures and time-varying effect-measure modifiers can be used in time-to-event models to investigate sport injury aetiology. We address four key-questions (i) Does time-to-event modelling allow change in training load to be included as a time-varying exposure for sport injury development? (ii) Why is time-to-event analysis superior to other analytical concepts when analysing training-load related data that changes status over time? (iii) How can researchers include change in training load in a time-to-event analysis? and, (iv) Are researchers able to include other time-varying variables into time-to-event analyses? We emphasise that cleaning datasets, setting up the data, performing analyses with time-varying variables and interpreting the results is time-consuming, and requires dedication. It may need you to ask for assistance from methodological peers as the analytical approaches presented this paper require specialist knowledge and well-honed statistical skills. Conclusion To increase knowledge about the association between changes in training load and injury, we encourage sports injury researchers to collaborate with statisticians and/or methodological epidemiologists to carefully consider applying time-to-event models to prospective sports injury data. This will ensure appropriate interpretation of time-to-event data.
FDA Approval Summary: Axicabtagene Ciloleucel for Relapsed or Refractory Large B-cell Lymphoma
Authors: Najat Bouchkouj, Yvette L. Kasamon, R. Angelo de Claro, Bindu George, Xue Lin, Shiowjen Lee, Gideon M. Blumenthal, Wilson Bryan, Amy E. McKee, Richard Pazdur
Journal: Clinical Cancer Research (2018)

Abstract In October 2017, the FDA granted regular approval to axicabtagene ciloleucel, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Efficacy was based on complete remission (CR) rate and duration of response (DOR) in 101 adult patients with relapsed or refractory large B-cell lymphoma (median 3 prior systemic regimens) treated on a single-arm trial. Patients received a single infusion of axicabtagene ciloleucel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine. The objective response rate per independent review committee was 72% [95% confidence interval (CI), 62–81], with a CR rate of 51% (95% CI, 41–62). With a median follow-up of 7.9 months, the median DOR was not reached in patients achieving CR (95% CI, 8.1 months; not estimable, NE), whereas patients with partial remission had an estimated median DOR of 2.1 months (95% CI, 1.3–5.3). Among 108 patients evaluated for safety, serious adverse reactions occurred in 52%. Cytokine release syndrome and neurologic toxicities occurred in 94% and 87% of patients, respectively, leading to implementation of a risk evaluation and mitigation strategy.
EPID-20. THE SURVIVAL BENEFIT OF VALPROIC ACID IN GLIOBLASTOMA TRENDS AWAY FROM SIGNIFICANCE WITH NEWER STUDIES: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Victor Lu, Pavlos Texakalidis, Kerrie McDonald
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is a dismal disease that presents often with seizure. The use of anti-epileptic medication valproic acid (VPA) has been suggested to provide survival benefit. This study aims to quantify the survival benefit of VPA in GBM on overall survival (OS) and determine if a trend in reported effect over time exists. Searches of 7 electronic databases from inception to April 2018 were conducted following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. There were 1498 articles identified for screening. Prognostic hazard ratios (HRs) derived from multivariate regression analysis were extracted and analyzed using meta-analysis of proportions and linear regression. Seven observational studies reporting prognostic HRs satisfied selection criteria. They described 3631 primary GBM diagnoses, with 603 (17%) receiving VPA in their treatment. VPA was shown to confer a statistically significant OS advantage the pooled cohort (HR, 0.709; 95% CI, 0.551–0.914; I2=60.1%; p=0.008) without specific bias concerns. However, this survival advantage trended towards null significance in newer studies (effect coefficient, 1.151; p=0.023). CONCLUSIONS: The current literature suggests that VPA confers a significant, prognostic OS advantage in GBM independent of other prognostic factors. This may be through a variety of possible biological mechanisms and clinical consequences. However, newer studies are significantly trending away from such a positive association, towards null significance. Larger, prospective randomized controlled studies are needed to validate if VPA itself provides true OS benefit in GBM patients.
ANGI-18. AUTOCRINE CYCLE OF BONE MORPHOGENETIC PROTEIN 4 (BMP4) ENHANCES TUMOR AGGRESSIVENESS IN IDH1-MUTATED GLIOMAS
Authors: Yiqiang Zhou, Yang Liu, Yanxin Lu, Di Yu, Fusheng Liu, Chunzhang Yang
Journal: Neuro-Oncology (2018)

IDH1 mutations are the most prevalent genetic abnormality in WHO Grade II/III glioma. IDH1-mutated glioma exhibits distinctive tumor biology, including oncogenesis, invasiveness and therapeutic sensitivity. BMP4, a member of TGFβ superfamily, has been reported to promote tumor progression and invasiveness in various types of malignancies. In the present study, we investigated BMP4 signaling in IDH1-mutated glioma, seeking for the underlying molecular mechanisms as well as possible therapeutic approaches by targeting BMP4 pathway. We analyzed the expression level of the BMP family in transcriptomic profiles of IDH1-mutated glioma. BMP4 expression was further quantified in clinical samples and patient-derived brain tumor initiating cells (BTIC). Further, we investigated the autocrine cycle of BMP4 to IDH1-mutated cells, focusing on the aggressive phenotype and cellular invasiveness. Finally, we analyzed the therapeutic value of BMP pathway inhibitors. Transcriptomic profiling showed significant up-regulation of BMP in IDH1-mutated glioma as compared with wild-type counterparts (8.20-fold for BMP2, 1.73-fold for BMP4). The up-regulation of BMP was confirmed in clinical samples through IHC. Moreover, we confirmed the up-regulation and secretion of BMP in IDH1-mutated BTIC. Autocrine of BMP not only activates concomitant Smad signaling, but also prompts cellular migration/invasion. Pharmacologic targeting BMP receptors by LDN-193189 suppressed Smad phosphorylation and cellular invasion. RNA sequencing and xenograft studies are currently ongoing to explore the molecular mechanism and therapeutic value of targeting BMP/Smad pathway for IDH1-mutated malignancies. CONCLUSION: Our preliminary findings showed that the BMP4 autocrine loop promotes the aggressiveness of IDH1-mutated glioma via Smad1 signaling. LDN-193189, the BMP receptor inhibitor, could be a potential therapeutic strategy to inhibit the aggressiveness of IDH1-mutated gliomas.
A Proinflammatory Gut Microbiota Increases Systemic Inflammation and Accelerates Atherosclerosis
Authors: Eelke Brandsma, Niels J. Kloosterhuis, Mirjam Koster, Daphne C. Dekker, Marion J.J. Gijbels, Saskia van der Velden, Melany Ríos-Morales, Martijn J.R. van Faassen, Marco G. Loreti, Alain de Bruin, Jingyuan Fu, Folkert Kuipers, Barbara M. Bakker, Marit Westerterp, Menno P.J. de Winther, Marten H. Hofker, Bart van de Sluis, Debby P.Y. Koonen
Journal: Circulation Research (2019)

Rationale: Several studies have suggested a role for the gut microbiota in inflammation and atherogenesis. A causal relation relationship between gut microbiota, inflammation, and atherosclerosis has not been explored previously. Objective: Here, we investigated whether a proinflammatory microbiota from Caspase1 −/− ( Casp1 −/− ) mice accelerates atherogenesis in Ldlr −/− mice. Method and Results: We treated female Ldlr −/− mice with antibiotics and subsequently transplanted them with fecal microbiota from Casp1 −/− mice based on a cohousing approach. Autologous transplantation of fecal microbiota of Ldlr −/− mice served as control. Mice were cohoused for 8 or 13 weeks and fed chow or high-fat cholesterol–rich diet. Fecal samples were collected, and factors related to inflammation, metabolism, intestinal health, and atherosclerotic phenotypes were measured. Unweighted Unifrac distances of 16S rDNA (ribosomal DNA) sequences confirmed the introduction of the Casp1 −/− and Ldlr −/− microbiota into Ldlr −/− mice (referred to as Ldlr −/− ( Casp1 −/− ) or Ldlr −/− ( Ldlr −/− ) mice). Analysis of atherosclerotic lesion size in the aortic root demonstrated a significant 29% increase in plaque size in 13-week high-fat cholesterol–fed Ldlr −/− ( Casp1 −/− ) mice compared with Ldlr −/− ( Ldlr −/− ) mice. We found increased numbers of circulating monocytes and neutrophils and elevated proinflammatory cytokine levels in plasma in high-fat cholesterol–fed Ldlr −/− ( Casp1 −/− ) compared with Ldlr −/− ( Ldlr −/− ) mice. Neutrophil accumulation in the aortic root of Ldlr −/− ( Casp1 −/− ) mice was enhanced compared with Ldlr −/− ( Ldlr −/− ) mice. 16S-rDNA-encoding sequence analysis in feces identified a significant reduction in the short-chain fatty acid–producing taxonomies Akkermansia , Christensenellaceae , Clostridium , and Odoribacter in Ldlr −/− ( Casp1 −/− ) mice. Consistent with these findings, cumulative concentrations of the anti-inflammatory short-chain fatty acids propionate, acetate and butyrate in the cecum were significantly reduced in 13-week high-fat cholesterol–fed Ldlr −/− ( Casp1 −/− ) compared with Ldlr −/− ( Ldlr −/− ) mice. Conclusions: Introduction of the proinflammatory Casp1 −/− microbiota into Ldlr −/− mice enhances systemic inflammation and accelerates atherogenesis.
EXTH-59. INTRACRANIAL IMPLANTATION OF TUMORICIDAL STEM CELL-SEEDED SCAFFOLDS AFTER GLIOBLASTOMA RESECTION
Authors: Kevin Sheets, Juli Rodriguez-Bago, Ivory Paulk, Shawn Hingtgen
Journal: Neuro-Oncology (2018)

The most common and aggressive primary brain cancer, glioblastoma (GBM), carries a life expectancy of 12–15 months. The short life expectancy is due, in part, to the inability of the current treatment, consisting of surgical resection followed by radiation and temozolomide, to eliminate invasive tumor foci. Treatment targeting invasive tumor foci may be advanced with tumoricidal human mesenchymal stem cells (MSCs). These cells exhibit potent tumor tropism and can be engineered to kill tumor cells in preclinical models. Advancements in preclinical models indicate surgical resection induces premature MSC loss and reduced therapeutic efficacy. Efficacy of MSC treatment can be improved by preloading MSCs on a biodegradable poly(lactic acid) (PLA) scaffold. MSC delivery on a PLA scaffold restores cell retention, persistence, and tumor killing. To study the effects of MSC-seeded PLA implantation on GBM, an accurate preclinical model is needed. Here we report a preclinical surgical method for performing image-guided tumor resection of GBM in immune-deficient mice followed by MSC-seeded scaffold transplantation. MSCs were engineered with lentiviral constructs to constitutively express and secrete the DR4/5 agonist TNFα-related apoptosis inducing ligand (TRAIL) as well as GFP to allow fluorescent tracking. Similarly, the human GBM tumor cells were engineered to express mCherry and Firefly luciferase, providing dual fluorescent/luminescent tracking capabilities. Using quantitative BLI, we found that maximal resection of visible fluorescent tumor cells failed to fully eradicate the tumor mass. Up to 10% of the pre-operative tumor signal intensity remained post-resection, mirroring observations in human patient testing. MSC-TRAIL implanted on PLA scaffolds were found to significantly suppress tumor recurrence, as animal survival improved 120% over control (13.5 vs 31 days). While used currently for investigating improvements to stem cell mediated delivery of therapeutics, this approach could be modified to research the impact of surgical resection on other therapeutic interventions.
Abstract 10773: Curcumin Improves the Outcomes of Cardiopulmonary Resuscitation in a Rat Model of Cardiac Arrest
Authors: Zhengfei Yang, Jiangang Wang, Lu Yin, Shen Zhao, Ziren Tang, Jena Cahoon, Wanchun Tang
Journal: Circulation (2015)

Introduction: Curcumin has been proven to provide potent protection of vital organs against regional ischemia reperfusion injury. In this study, we investigated the effects of curcumin on the outcomes of CPR in a rat model of cardiac arrest. Hypothesis: Curcumin reduces the severity of post-CPR myocardial dysfunction and prolong the duration of survival. Method: Sixteen male Sprague-Dawley rats weighing between 450-550g were randomized into two groups: 1) Placebo; 2) Curcumin (100 mg/kg) pre-treatment. Ventricular fibrillation (VF) was induced. After 8 mins of VF, CPR was initiated for 8 mins and defibrillation was then attempted. Myocardial function was measured by echocardiography at baseline and hourly for 4 hours following successful resuscitation. The duration of survival was observed for total 72 hours. Result: Six animals in the placebo group and seven in the curcumin group were successfully resuscitated. Post-resuscitation myocardial function was significantly impaired in all animals. However, myocardial function gradually improved 4 hours after resuscitation and was significantly better in the animals pre-treated with curcumin (Figure). Significantly shorter duration of survival of 40±29 hours was observed in the placebo group. Conclusion: In a rat model of cardiac arrest, curcuminim proves post-resuscitation myocardial dysfunction and prolongs the duration of survival.
Abstract 16715: Incidence of Atrial Fibrillation After Atrial Flutter Ablation: A Meta-analysis Study
Authors: Maria Isabel Pino, Karam Ayoub, Oscar L Llanos, Ramez Nairooz, Amjad Abualsuod, Abdul Hakeem, Naga V Pothineni, Hakan Paydak, Waddah Maskoun
Journal: Circulation (2015)

Background: Atrial Flutter (AFL) is usually initiated with short bursts of Atrial Fibrillation (AF). The incidence rate of AF after AFL ablation is variable. We evaluated the occurrence of AF in patients who underwent successful AFL catheter ablation with documented prior AF versus no prior AF. Methods: A meta-analysis was performed by searching online databases from January 1996 to April 2015 for studies describing patients who underwent typical AFL catheter ablation with and without prior AF. Results: A total of 36 articles were included, describing 6567 patients with typical AFL (2753 with prior AF and 3814 with no prior AF) who underwent ablation with 95% average success rate (bidirectional block). The overall incidence of AF after ablation was 35.3% (41% prior to ablation) during mean weighted follow-up (f/u) duration of 29.4 months. AF incidence after AFL ablation was 23% in patients with no prior AF and 52% in those with prior AF (OR 3.96, 95% CI [3.174.95] ; p&lt;0.00001). Subgroup analysis based on duration of f/u showed a significant variation of this probability (p=0.0003) between the group with &lt; 2 years f/u, compared to &gt; 2 years f/u due to an increase of AF incidence rate in patients with no prior AF. In studies with &lt; 2 years f/u duration, AF weighted average incidence rate after AFL ablation was 53.6 % in patients with prior AF and 14.3% in those with no prior AF (OR 6.90, 95% CI [4.5410.48] ; p&lt;0.00001). In studies with &gt; 2 years f/u duration, post-ablation AF developed in 51.3% of those with prior AF and in 26.3% of those with no prior AF (OR 2.93, 95% CI [2.423.56] ; p&lt;0.00001). Figure 1 Conclusions: Patients with prior history of AF have a higher incidence of AF after AFL ablation when compared to patients with no prior history of AF. However, this significantly decreases with extended follow-up duration due to an increase of detected AF in patients with no prior history of AF. This finding is important for decisions regarding anticoagulation plan after successful AFL ablation.
IMMU-65. IL-6 DRIVES ALTERNATIVE MACROPHAGE ACTIVATION AND IMMUNE SUPPRESSION IN GLIOBLASTOMA THROUGH PPARγ/HIF-2α
Authors: Hao Duan, Steven Brem, Yanqing Gong, Yi Fan
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in humans. Immunotherapy holds great promise for GBM treatment. However, current immunotherapy of solid tumors, primarily by targeting tumor-associated T cells, remains a big challenge, largely due to limited T cell infiltration and activation in the immunosuppressive microenvironment. Here our work reveals a macrophage-dependent mechanism for tumor immunosuppression, by which IL-6 induces alternative macrophage activation in GBM microenvironment. We show that IL-6 induces robust arginase-1 expression and macrophage alternative activation, mediated through Akt/mTOR/peroxisome proliferator-activated receptor (PPAR)-γ-dependent transcriptional activation of hypoxia-inducible factor (HIF)-2α. Furthermore, genetic ablation of IL-6 abrogates macrophage alternative activation, inhibits tumor growth and progression, enhances tumor-associated T cells’ activity, and improves animal survival in a genetically engineered mouse GBM model. Notably, administration of anti-IL6 neutralizing antibody remarkedly reverses tumor immune suppression and promotes infiltration of T cells and neutrophils, leading to inhibited tumor growth and improved animal survival in the GBM-bearing mice. Finally, analysis of TCGA database suggests that high expression of IL-6 correlates with poor overall survival in human patients with low-grade glioma and GBM. Taken together, our findings suggest that IL-6 blockade may offer exciting opportunities for reversing immunosuppression in GBM, serving as a stand-alone therapeutic strategy or a combined treatment with T cell-based immunotherapy.
Limitations of resting haemodynamics in chronic thromboembolic disease without pulmonary hypertension
Authors: Emilia Maria Swietlik, Alessandro Ruggiero, Andrew J. Fletcher, Dolores Taboada, Emily Knightbridge, Louise Harlow, Ian Harvey, Nicholas Screaton, John E. Cannon, Karen K.K. Sheares, Choo Ng, David P. Jenkins, Joanna Pepke-Zaba, Mark R. Toshner
Journal: European Respiratory Journal (2018)

There is renewed interest in the haemodynamic definitions of pulmonary hypertension (PH), reigniting an old debate about diagnostic thresholds [1]. Recent prospective data support work dating back over 40 years demonstrating patients with "borderline" PH (mean pulmonary artery pressure (mPAP) <25 mmHg) can still have significant morbidity and mortality [2]. Therefore, lowering the mPAP threshold for the diagnosis of precapillary pulmonary arterial hypertension (PAH) has been discussed at World Symposium on Pulmonary Hypertension in Nice, France, in 2018. A potentially different approach has arisen in group 4 (chronic thromboembolic pulmonary hypertension (CTEPH)), where the concept of chronic thromboembolic disease without PH (CTED) has gained traction. Chronic thromboembolic disease (CTED) without pulmonary hypertension is emerging as a new and important disease classification <http://ow.ly/ZmK730mv5Xh>