tbuckley/cabot-search huggingface dataset:
OS09.7 Phase III radomized trial of autologous cytokine-induced killer cell immunotherapy for newly diagnosed glioblastoma in Korea
Authors: C. Kim, D. Nam, D. Kong, S. Kang, J. Jang, J. Kim, Y. Lim, Y. Koh, Y. Chung, J. Kim
Journal: Neuro-Oncology (2017)

Introduction: Adoptive cell immunotherapy involves an ex vivo expansion of autologous cytokine-induced killer (CIK) cells before their reinfusion into the host. We evaluated the efficacy and safety of CIK cell immunotherapy with radiotherapy-temozolomide (TMZ) for the treatment of newly diagnosed glioblastomas. Materials and Methods: In this multi-center, open-label, phase 3 study, we randomly assigned patients with newly diagnosed glioblastoma to receive CIK cell immunotherapy combined with standard TMZ chemoradiotherapy (CIK immunotherapy group) or standard TMZ chemoradiotherapy alone (control group). The efficacy endpoints were analyzed in the intention-to-treat set and in the per protocol set. Results: Between December 2008 and October 2012, a total of 180 patients were randomly assigned to the CIK immunotherapy (n = 91) or control group (n = 89). In the intention-to-treat analysis set, median PFS was 8.1 months [95% confidence interval (CI), 5.8 to 8.5 months] in the CIK immunotherapy group, as compared to 5.4 months (95% CI, 3.3 to 7.9 months) in the control group (one-sided log-rank, p = 0.0401). Overall survival did not differ significantly between two groups. Grade 3 or higher adverse events, health-related quality of life and performance status between two groups did not show a significant difference. Conclusions: The addition of CIK cells immunotherapy to standard chemoradiotherapy with TMZ improved PFS. However, the CIK immunotherapy group did not show evidence of a beneficial effect on overall survival.
Tumor Antigen Vaccination of Donors to Augment Graft-Versus-Tumor Effects after Allogeneic Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide
Authors: Han-Hsuan Fu, Jie Wang, Jie Fu, Richard J Jones, Hyam Levitsky, Ephraim J. Fuchs
Journal: Blood (2016)
P04.22 Diffusivity changes in bevacizumab-responding and refractory meningioma
Authors: U. Roelcke, J. Berberat, C. Mamot, L. Remonda
Journal: Neuro-Oncology (2017)

Introduction: Meningiomas may be highly vascularized and therefore respond to antiangiogenic treatment such as bevacizumab (Bev). Here we report on the time course of diffusivity as surrogate of tumor cell density and ischemic tissue changes in a patient with multiple intra- and extracranial meningiomas WHO grade III. Tumors initially responded to Bev, but were refractory at second Bev exposure. Materials and Methods: A 73 years old patient was studied at the time of 7th tumor recurrence. Size and diffusivity (apparent diffusion coefficient, ADC) of six meningiomas were quantified using ROI analysis on gadolinium-enhanced T1-weighted and corresponding diffusion weighted MRI. Bev treatment was delivered every two weeks with a dose of 10 mg/kg per infusion. Results: Mean tumor size increased 3.5-fold during spontaneous growth over 3.5 months, which was paralleled by an ADC decrease from 750 ± 214 to 644 ± 83*10-6mm2/s (mean±SD). The first Bev treatment period led to a response of all six meningiomas and induced a peak tumor size decrease of 70% at seven months. During that period ADC values increased 1.4-fold reaching a maximum already at 2 months. After seven months Bev had to be discontinued due to limb edema and proteinuria. Without Bev tumor size again increased 2.7-fold over seven months. Therefore Bev treatment was resumed, however, during the second treatment period of 4 months tumor size further increased, but ADC values remained unchanged (mean 1030 ± 321*10-6mm2/s). DISCUSSION: Successful Bev exposure lead to an early ADC increase which may be attributed to ischemic tumor damage and a decrease of tumor cell density. Vice versa, ADC remained unchanged during Bev resistence which indicates that ADC measurement may predict antiangiogenic treatment response or failure. This issue has to be addressed in a larger study. If confirmed ADC may be used to individualize meningioma treatment with Bev.
Abstract 306: Sympathetic Reinnervation is Required for Mammalian Cardiac Regeneration.
Authors: Ian A White, Julie Gordon, Wayne Balkan, Joshua M Hare
Journal: Circulation Research (2015)

Rationale: Established animal models of limb and tissue regeneration with re-vascularization demonstrate a critical dependence on concurrent reinnervation by the peripheral nervous system. Objective: Considering the significant abundance of autonomic nerves in the mammalian heart we tested the hypothesis that reinnervation is required for neonatal mouse cardiac regeneration. Methods and Results: Crossing Wnt1:cre transgenic mice with a double-tandem (td) tomato reporter strain identifies all neural crest-derived cell lineages including the peripheral autonomic nerves in the heart. Whole mount epi-fluorescence microscopy facilitated the clear resolution of subepicardial autonomic nerves in the mouse ventricles providing unprecedented detail of the subepicardial neuroanatomy of the mouse heart. Sympathetic nerve bundles envelop the entire heart and extend to the tip of the ventricular apex. Our data demonstrate that during regeneration of the resected ventricular apex of the neonatal mouse heart, sympathetic nerves fibers undergo concurrent re-growth into the injury site resulting in complete sympathetic reinnervation of the regenerated tissue. Sympathectomy of the heart, induced by administration of 6-OHDA, was sufficient to block innate cardiac regeneration in the neonatal mouse. Conclusions: We report that the innate ability of the neonatal mouse heart to undergo regeneration in response to injury is dependent on sympathetic innervation of the ventricular myocardium. Ablation of post-ganglionic sympathetic nerves blocks the innate regenerative capacity of neonatal mouse hearts suggesting that sympathetic reinnervation is critical for ventricular regeneration. This finding has significant implications for adult regeneration following myocardial infarction where nerve growth is hindered by age related influences and scar tissue.
Change in non-abstinent WHO drinking risk levels and alcohol dependence: a 3 year follow-up study in the US general population
Authors: Deborah S Hasin, Melanie Wall, Katie Witkiewitz, Henry R Kranzler, Daniel Falk, Raye Litten, Karl Mann, Stephanie S O'Malley, Jennifer Scodes, Rebecca L Robinson, Raymond Anton, Joanne Fertig, Keith Isenberg, David McCann, Didier Meulien, Roger Meyer, Charles O'Brien, Megan Ryan, Bernard Silverman, Francoise Trinquet, Conrad Wong, Benjamine Zakine
Journal: The Lancet Psychiatry (2017)
Abstract P145: Cathelicidin Antimicrobial Peptide Is Upregulated After Myocarditis and Inhibits Fibroblast Migration via P2x7 Receptor Signaling
Authors: Hiroyuki Nakayama, Kazuki Matsui, Tomomi Yamashita, Haruyo Kawaguchi, Yasushi Fujio
Journal: Circulation Research (2011)

Rationale _ Experimental autoimmune myocarditis in BALB/c mice is a model of inflammatory heart disease. It is well known that the process of this model exhibits the acute inflammation phase followed by the healing phase. However, the precise mechanisms how the inflammation terminates and the healing proceeds remain to be elucidated. Objective _ To identify the molecule which functions in the healing phase of EAM and investigate its pathophysiological roles on cardiac cells. Methods and Results _ To induce EAM, BALB/c mice were immunized twice with α-myosin heavy chain peptide. The severity of inflammation peaked at 21days after immunization and mitigated at 28days. To analyze the alterations of gene expression profile during healing phase, we performed microarray analyses using mRNA from hearts of 21day and 28day after immunization. Among up-regulated genes, we focused on cathelicidin antimicrobial peptide (CAMP) which has been reported to be involved in anti-inflammatory response and epithelial tissue repair. Histochemical staining using anti-CAMP antibody revealed that CAMP expresses in inflammatory cells in EAM hearts. Treatment with LL37, a human homologue of CAMP, mediated activation of ERK, JNK and p38 in fibroblasts from neonatal rat hearts, whereas it failed to activate those MAP kinases in rat neonatal cardiomyocytes, suggesting CAMP is engaged in healing process by regulating function of fibroblasts. In addition, LL–37 treatment mediated morphological changes of fibroblasts and decreased migration distances assessed by wound healing assay as well (283±43 mm in treated cells vs 183±54 mm in cells treated with 10 mg/ml of LL37, p&lt;0.01). The expression of focal adhesion kinase is decreased in LL37 treated cardiac fibroblasts compared with non-treated cells. Moreover, blockade of P2X7 receptor which is known as a receptor for LL37 restored the migration distances after LL37 treatment, suggesting that LL37 suppresses cardiac fibroblast motility via P2X7 receptor signaling. Conclusion _ Our results indicate that CAMP is up-regulated after myocarditis and inhibits fibroblasts migration via P2X7 receptor signaling. Those results suggest that CAMP could be a useful tool to inhibit fibrotic changes in inflammatory heart disease.
Cancer diagnostic centres must have high throughput
Authors: S Michael Crawford
Journal: BMJ (2017)

Simon Stevens’s plan for cancer diagnosis includes setting up new multidisciplinary Rapid Diagnostic and Assessment Centres, 10 within the year and more to follow by 2019.12 The name of these facilities echoes a service at the Royal Marsden Hospital, which focuses on patients with suspected breast, skin, or prostate cancer.

Enhancement of …
P08.39 Combined in-silico and on-chip validation of pseudopalisade formation hypothesis in Glioblastoma
Authors: A. Martínez-González, J. M. Ayuso, R. Monge, M. Virumbrales-Muñoz, G. A. Llamazares, A. Hernández-Laín, P. Sánchez-Gómez, V. M. Pérez-García, L. J. Fernández, I. Ochoa
Journal: Neuro-Oncology (2017)

Introduction: Hypercellular regions surrounding necrotic areas in glioblastoma (GBM), named pseudopalisades, are characteristic of these tumors and have been hypothesized to be waves of migrating GBM cells. These structures are thought to be induced by oxygen depletion caused by the accumulation of cells far from nutrient supplies (chronic hypoxia) and/or tumor-induced blood vessel occlusion (acute hypoxia). The universal appearance of these structures in GBM suggests that they may play an instrumental role in their spreading and invasion. However the validation of the mechanisms of pseudopalisade formation has remained challenging. Materials and methods: A mathematical model was developed incorporating the main mechanisms of pseudopalisade formation. Oxygen coming from straight vessels drives phenotype changes. A third phenotype was included accounting for hypoxic cells switching back to a more proliferative phenotype in regions of normoxia. Experiments were done by embedding different densities of U-251 MG cells within a collagen hydrogel in a custom-designed microfluidic device. By controlling the medium flow through lateral microchannels, we mimic and control blood-vessel obstruction events associated with this disease. Results: Nutrient and oxygen starvation triggered a strong migratory process leading to pseudopalisade generation in silico and in vitro. Also, cells at greatest distance from oxygen supply became hypoxic after a critical point in tumor growth was reached (due to increased metabolism) forming pseudopalisades both in silico and in vitro. All the elements included in the mathematical model were necessary to describe both types of phenomena pointing out to the insufficiency of the go-or-grow hypothesis to describe pseudopalisade formation on-chip. Conclusions: Using a combination of computational and experimental techniques, we proved the feasibility of the two hypotheses of pseudopalisade formation, driven by either acute or chronic hypoxia. Additionally, we verified the potential of microfluidic devices as advanced artificial systems capable of experimentally modeling nutrient and oxygen gradients during tumor evolution. FUNDING: National Research Program, Spain (BIO2016-79092-R, DPI2015-65401-C3-1-R, MTM2012-31073, bes-2012-059940, PI12/00775, PI13/01258 and RD12/0036/0027); FEDER Spain [MTM2015-71200-R]. Junta de Comunidades de Castilla-La Mancha, Spain [PEII-2014-031-P]. James S. Mc. Donnell Foundation, USA (220020420 and 220020450).
Revealing the Tumor Ecosystem in Follicular Lymphoma By Mass Cytometry
Authors: Xuehai Wang, Manabu Kusakabe, Deanne Gracias, Guillermo Simkin, Ainsleigh Hill, Robert Kridel, Justin Meskas, David W Scott, Christian Steidl, Randy D Gascoyne, Ryan R. Brinkman, Andrew P. Weng
Journal: Blood (2016)
P10.03 Management of low-grade glioma: a systematic review and meta-analysis
Authors: T. J. Brown, D. Bota, E. Maher, D. Aregawi, L. M. Liau, J. Buckner, M. Weller, M. J. van den Bent, M. S. Berger, M. Glantz
Journal: Neuro-Oncology (2017)

Introduction: Low-grade gliomas (LGG, WHO grade I-II) account for 16.9-22% of all primary brain tumors. Management of these tumors consists of surgery, sometimes followed by radiation and/or chemotherapy. A rigorous, quantitative evaluation of the literature investigating the management of LGG has never been published. Methods: We conducted an exhaustive, PRISMA-compliant systematic review of the literature from January 1966 to September 2016 comparing the association of chemotherapy, radiation, or extent of resection with survival and progression-free survival at 2, 5, and 10 years in LGG. Included studies were graded for quality using AAN criteria. Pre-specified data were extracted and summary statistics were calculated using the inverse variance method and random effects model. Results: Five studies (n=567) report on LGG patients treated with chemotherapy. The relative risk (RR) and 95% confidence intervals [95% CI] for death (chemotherapy vs. no chemotherapy) at 2, 5, and 10 years was 1.34 [0.85-2.12], 0.83 [0.64-1.09], and 0.77 [0.58-1.03]. RR for progression at 2, 5, and 10 years was 0.92 [0.64-1.33], 0.69 [0.55-0.87, p=0.001], and 0.58 [0.39-0.87, p=0.008]. A sensitivity analysis of OS including only class I and II studies showed a RR of death (chemotherapy vs. no chemotherapy) at 2, 5, and 10 years of 1.23 [0.72-2.08], 0.78 [0.58-1.05, p=0.1], and 0.69 [0.56-0.86, p=0.0006]. Among only IDH1-mutated patients, the RR of progression with chemotherapy compared to control at 2, 5, and 10 years was 0.48 [0.06-4.1], 0.27 [0.08-0.84, p=0.02], and 0.21 [0.03-1.59]. Ten studies (n=1918) provide data regarding the effect of post-operative radiation vs. delayed or no radiation. RR and 95% CI for death at 2, 5, and 10 years was 0.92 [0.53-1.58], 0.93 [0.60-1.43], and 0.99 [0.69-1.41]. RR for progression at 2, 5, and 10 years was 0.66 [0.51-0.86, p=0.002], 0.73 [0.61-0.88, p=0.0008], and 0.74 [0.60-0.91, p=0.005]. Twenty-three studies (n=3891) compare gross total resection (GTR) vs. subtotal resection (STR) in LGG. RR and 95% CI of death at 2, 5, and 10 years (GTR vs. STR) was 0.29 [0.17-0.52, p<0.0001], 0.39 [0.29-0.51, p<0.00001], and 0.50 [0.35-0.70, p<0.0001]. RR of progression (GTR vs. SR) at 2, 5, and 10 years was 0.37 [0.24-0.57, p<0.0001], 0.50 [0.39-0.64, p<0.0001], and 0.67 [0.53-0.84, p=0.0005]. Relevant prognostic factors were also analyzed. For all three treatment subsets combined, only 6 studies provided class I or II evidence, and then only for the OS endpoint. Conclusions: This analysis, the largest systematic review and only quantitative systematic review performed on these questions, suggests that early post-operative radiation and chemotherapy may improve PFS in patients with LGG. Chemotherapy may also improve OS. GTR (compared with STR) is associated with substantially improved OS and PFS. Due to the lack of high quality prospective trials, additional rigorous studies are needed.
Trends in Infective Endocarditis in California and New York State, 1998-2013
Authors: Nana Toyoda, Joanna Chikwe, Shinobu Itagaki, Annetine C. Gelijns, David H. Adams, Natalia N. Egorova
Journal: JAMA (2017)

Prophylaxis and treatment guidelines for infective endocarditis have changed substantially over the past decade. In the United States, few population-based studies have explored the contemporary epidemiology and outcomes of endocarditis.To quantify trends in the incidence and etiologies of infective endocarditis in the United States.Retrospective population epidemiology study of patients hospitalized with a first episode of endocarditis identified from mandatory state databases in California and New York State between January 1, 1998, and December 31, 2013.Infective endocarditis.Outcomes were crude and standardized incidence of endocarditis and trends in patient characteristics and disease etiology. Trends in acquisition mode, organism, and mortality were analyzed.Among 75 829 patients with first episodes of endocarditis (mean [SD] age, 62.3 [18.9] years; 59.1% male), the standardized annual incidence was stable between 7.6 (95% CI, 7.4 to 7.9) and 7.8 (95% CI, 7.6 to 8.0) cases per 100 000 persons (annual percentage change [APC], -0.06%; 95% CI, -0.3% to 0.2%; P = .59). From 1998 through 2013, the proportion of patients with native-valve endocarditis decreased (from 74.5% to 68.4%; APC, -0.7%; 95% CI, -0.9% to -0.5%; P < .001). Prosthetic-valve endocarditis increased (from 12.0% to 13.8%; APC, 1.3%; 95% CI, 0.8% to 1.7%; P < .001), and cardiac device-related endocarditis increased (from 1.3% to 4.1%; APC, 8.8%; 95% CI, 7.8% to 9.9%; P < .001). The proportion of patients with health care-associated nosocomial endocarditis decreased (from 17.7% to 15.3%; APC, -1.0%; 95% CI, -1.4% to -0.7%; P < .001). The proportion of patients with health care-associated nonnosocomial endocarditis increased (from 32.1% to 35.9%; APC, 0.8%; 95% CI, 0.5% to 1.1%; P < .001). The incidence of oral streptococcal endocarditis did not increase (unadjusted: APC, -0.1%; 95% CI, -0.8% to 0.6%; P = .77; adjusted: APC, -1.3%; 95% CI, -1.8% to -0.7%; P < .001). Crude 90-day mortality was unchanged (from 23.9% to 24.2%; APC, -0.3%; 95% CI, -1.0% to 0.4%; P = .44); adjusted risk of 90-day mortality decreased (adjusted hazard ratio per year, 0.982; 95% CI, 0.978 to 0.986; P < .001).In California and New York State, the overall standardized incidence of infective endocarditis was stable from 1998 through 2013, with changes in patient characteristics and etiology over this time.
MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure
Authors: Evangelos Triantafyllou, Oltin T Pop, Lucia A Possamai, Annika Wilhelm, Evaggelia Liaskou, Arjuna Singanayagam, Christine Bernsmeier, Wafa Khamri, Gemma Petts, Rebecca Dargue, Scott P Davies, Joseph Tickle, Muhammed Yuksel, Vishal C Patel, Robin D Abeles, Zania Stamataki, Stuart M Curbishley, Yun Ma, Ian D Wilson, Muireann Coen, Kevin J Woollard, Alberto Quaglia, Julia Wendon, Mark R Thursz, David H Adams, Chris J Weston, Charalambos G Antoniades
Journal: Gut (2017)

Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response.Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer-/-) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice.We demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF, APAP-treated Mer-/- mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance.We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.
Abstract 345: R403Q Mutation Increases the Rate of Force Redevelopment in 2 Month Mice
Authors: Camille Birch, John P Konhilas
Journal: Circulation Research (2013)

Familial hypertrophic cardiomyopathy is a primary disease of the sarcomere. The R403Q mutation resides at the actin-interaction site on myosin and leads to progressive hypertrophic cardiomyopathy which progresses towards heart failure. Along with deteriorating cardiac function, these hearts experience an overall change in metabolic landscape, suggesting altered energetic function in hearts that express the R403Q mutation. We tested the hypothesis that the R403Q mutation intrinsically increases the energetic cost of contraction. To do this, we determined myofilament function in demembranated cardiac trabeculae from male wild-type (WT) and R403Q mice at 2 months of age, prior to overt signs of cardiac pathology. Firstly, steady-state Ca2+ sensitivity of force generation was not significantly different between male R403Q (n=4) and WT counterparts (n=2) consistent with previous findings. Secondly, the rate of force redevelopment (ktr) in skinned cardiac tissue was measured following unloaded isotonic shortening and a rapid re-stretch to 15% of the original muscle length at a sarcomere length of 2.0μm. R403Q mice display an increased rate of force redevelopment (49.89 s-1 ± 8.13, n = 4) compared to WT counterparts (24.52 ± 4.29, n = 6) at maximal activation indicating an increase in the apparent rates of crossbridges entering and leaving force-generating states (p &lt; 0.05). In conclusion, the R403Q mutation does not impact steady-state Ca2+ sensitivity of force but increases total crossbridge cycling rate suggesting a higher energy cost of force generation. Future studies are aimed at determining the energetic cost of contraction in R403Q hearts and how this increased energetic cost leads to hypertrophic cardiomyopathy.