tbuckley/cabot-search huggingface dataset:
The prevalence of radiographic and MRI-defined patellofemoral osteoarthritis and structural pathology: a systematic review and meta-analysis
Authors: Harvi F Hart, Joshua J Stefanik, Narelle Wyndow, Zuzana Machotka, Kay M Crossley
Journal: British Journal of Sports Medicine (2017)

Patellofemoral osteoarthritis (PF OA) is more prevalent than previously thought and contributes to patient's suffering from knee OA. Synthesis of prevalence data can provide estimates of the burden of PF OA.This study aims to conduct a systematic review and meta-analysis on the prevalence of PF OA and structural damage based on radiography and MRI studies in different populations.We searched six electronic databases and reference lists of relevant cross-sectional and observational studies reporting the prevalence of PF OA. Two independent reviewers appraised methodological quality. Where possible, data were pooled using the following categories: radiography and MRI studies.Eighty-five studies that reported the prevalence of patellofemoral OA and structural damage were included in this systematic review. Meta-analysis revealed a high prevalence of radiographic PF OA in knee pain or symptomatic knee OA (43%), radiographic knee OA or at risk of developing OA (48%) and radiographic and symptomatic knee OA (57%) cohorts. The MRI-defined structural PF damage in knee pain or symptomatic population was 32% and 52% based on bone marrow lesion and cartilage defect, respectively.One half of people with knee pain or radiographic OA have patellofemoral involvement. Prevalence of MRI findings was high in symptomatic and asymptomatic population. These pooled data and the variability found can provide evidence for future research addressing risk factors and treatments for PF OA.PROSPERO systematic review protocol (CRD42016035649).
P01.10 Dock4 heterozygous deletion normalizes the glioblastoma microenvironment &amp; improves response to radiation
Authors: T. Egnuni, S. Short
Journal: Neuro-Oncology (2017)

Introduction: Invasion and growth of brain tumours require cooperation of the tumour cell and endothelial cell compartments. Limited efficacy of anti-angiogenic therapy in glioblastoma is associated with activation of VEGF independent mechanisms, and the development of hypoxia. Those can be overcome by targeting intracellular signaling pathways, and designing strategies for blood vessel normalization. Here we investigate the role of the Rac1 exchange factor Dock4, a regulator of the small GTPase Rac1, in cancer cell invasion and the microenvironment of glioblastoma. Materials and Methods: We assessed Dock4 expression in glioblastoma patient samples. The invasive potential of cancer cells with Dock4 knockdown was tested in spheroid assays in collagen matrix. To investigate the role of Dock4 in the microenvironment, the murine glioma cell line CT2A was injected intracranially into Dock4 heterozygous mice and wild type mice. Mice of each genotype were randomly allocated into two groups: control or treatment with radiation therapy, 2Gy daily x 5 days or 5 Gy daily x 3 days, delivered using an image guided small animal irradiation platform (SARRP). Results: We demonstrate that Dock4 expression in patient samples was associated with high nestin positivity. Knocking down Dock4 suppressed invasion of patient derived neurospheres in collagen. Heterozygous Dock4 genetic deletion in the microenvironment reduced blood vessel size, and reversed morphological abnormalities including the lining of blood vessels by cancer cells in syngeneic tumours. In this pilot study, tumours growing in Dock4 heterozygous mice showed improved response to radiation compared to tumours growing in wild type mice. Conclusions: These findings ­suggest that targeting the Dock4 pathway may provide a means of improving radiotherapy by normalizing the blood vessels, which may provide a therapeutic opportunity in parallel with inhibiting glioblastoma invasion.
Preliminary Results from a Phase 1/2 Study of DSP-7888, a Novel WT1 Peptide-Based Vaccine, in Patients with Myelodysplastic Syndrome (MDS)
Authors: Shigesaburo Miyakoshi, Kensuke Usuki, Itaru Matsumura, Yasunori Ueda, Hiromi Iwasaki, Toshihiro Miyamoto, Makoto Origuchi, Shuzo Tagashira, Ichiro Naoi, Tomoki Naoe, Masahiro Kizaki, Yuji Heike, Koichi Akashi, Yasushi Miyazaki
Journal: Blood (2016)
DNA methylation of a novel PAK4 locus influences ototoxicity susceptibility following cisplatin and radiation therapy for pediatric embryonal tumors
Authors: Austin L Brown, Kayla L Foster, Philip J Lupo, Erin C Peckham-Gregory, Jeffrey C Murray, M Fatih Okcu, Ching C Lau, Surya P Rednam, Murali Chintagumpala, Michael E Scheurer
Journal: Neuro-Oncology (2017)

Ototoxicity is a common adverse side effect of platinum chemotherapy and cranial radiation therapy; however, individual susceptibility is highly variable. Therefore, our objective was to conduct an epigenome-wide association study to identify differentially methylated cytosine-phosphate-guanine (CpG) sites associated with ototoxicity susceptibility among cisplatin-treated pediatric patients with embryonal tumors.Samples were collected for a discovery cohort (n = 62) and a replication cohort (n = 18) of medulloblastoma and primitive neuroectodermal tumor patients. Posttreatment audiograms were evaluated using the International Society of Paediatric Oncology (SIOP) Boston Ototoxicity Scale. Genome-wide associations between CpG methylation and ototoxicity were examined using multiple linear regression, controlling for demographic and treatment factors.The mean cumulative dose of cisplatin was 330 mg/m2 and the mean time from end of therapy to the last available audiogram was 6.9 years. In the discovery analysis of 435233 CpG sites, 6 sites were associated with ototoxicity grade (P < 5 × 10-5) after adjusting for confounders. Differential methylation at the top CpG site identified in the discovery cohort (cg14010619, PAK4 gene) was replicated (P = 0.029) and reached genome-wide significance (P = 2.73 × 10-8) in a combined analysis. These findings were robust to a sensitivity analysis evaluating other potential confounders.We identified and replicated a novel CpG methylation loci (cg14010619) associated with ototoxicity severity. Methylation at cg14010619 may modify PAK4 activity, which has been implicated in cisplatin resistance in malignant cell lines.
Effect of anti‐IgE in occupational asthma caused by exposure to low molecular weight agents
Authors: M. Ollé‐Monge, M.J. Cruz, S. Gomez‐Ollés, I. Ojanguren, J. Vanoirbeek, X. Muñoz
Journal: Allergy (2017)

The role of immunoglobulin (Ig)-E in occupational asthma (OA) due to low molecular weight (LMW) agents is not well established compared to classical atopic asthma. In this study, we evaluate whether anti-IgE monoclonal antibody (mAb) has an effect in a mouse model of OA, using persulfate salts.On days 1 and 8, BALB/C mice were dermally sensitized with 5% ammonium persulfate (AP) or dimethyl sulfoxide (DMSO). On days 15, 18, and 21, animals were injected intraperitoneally with anti-IgE mAb or PBS 6 hours before challenge with AP or saline. Airway hyper-responsiveness (AHR) using a methacholine test, airway inflammation in bronchoalveolar lavage (BAL) and lung tissue, and total free IgE in serum samples were analyzed 24, 48, and 96 hours after the last challenge.Anti-IgE mAb treatment almost completely neutralized free serum IgE. In AP-sensitized and challenged mice, anti-IgE mAb treatment abolished AHR 24 hour and 48 hour after the last challenge and significantly reduced the total number of eosinophils and neutrophils 48 hour and 96 hour after the last AP challenge compared with nontreated mice. Levels of interleukin (IL)-13 in BAL were also significantly decreased after anti-IgE administration 24 hour and 48 hour after the last AP challenge. Histological analysis of the lung sections from anti-IgE-treated mice revealed normal inflammatory patterns similar to control groups 48 hour after the last challenge.Anti-IgE-treated mice showed a significant improvement in asthma features related to the AHR and airway inflammation. Anti-IgE mAb has positive effects in OA induced by persulfate salts.
Assembly of polymer micelles through the sol-gel transition for effective cancer therapy
Authors: Nisar Ul Khaliq, Keun Sang Oh, Febrina Carolina Sandra, Yeonhee Joo, Juhyung Lee, Youngro Byun, In-San Kim, Ick Chan Kwon, Jae Hong Seo, Sang Yoon Kim, Soon Hong Yuk
Journal: Journal of Controlled Release (2017)
Acanthamoeba keratitis - Multiple states, 2005-2007
Authors: K. Bryant, T. Chang, S. Chen, J. Rosenberg, R. Hammond, K. McConnell, R. Sanderson, J. Elm, M. Nakata, C. Wakida, C. Austin, J. Bestudik, M. G. Bordson, C. Conover, L. Granzow, A. Pelletier, V. Rea, A. Chu, E. Luckman, K. Signs, J. Harper, T. Damrow, E. Mosher, K. Kruger, E. Saheli, M. Cassidy, J. Hatch, A. Weltman, E. J. Garcia Rivera, Y. Garcia, M. A. Kainer, J. Archer, C. Joslin, P. Cernoch, D. Jones, M. Hamill, A. Matoba, S. Pflugfelder, K. Wilhelmus, S. Beavers, T. Chen, K. Christian, M. Cooper, D. Dufficy, M. Gershman, M. Glenshaw, A. Hall, S. Holzbauer, A. Huang, A. Langer, Z. Moore, A. S. Patel, L. R. Carpenter, J. Schaffzin, J. Su, I. Trevino, T. Weiser, P. Wiersma, S. Lorick, J. R. Verani
Journal: MMWR Morbidity and Mortality Weekly Report (2007)
3D additive-manufactured nanocomposite magnetic scaffolds: Effect of the application mode of a time-dependent magnetic field on hMSCs behavior
Authors: Ugo D'Amora, Teresa Russo, Antonio Gloria, Virginia Rivieccio, Vincenzo D'Antò, Giacomo Negri, Luigi Ambrosio, Roberto De Santis
Journal: Bioactive Materials (2017)

Over the past few years, the influence of static or dynamic magnetic fields on biological systems has become a topic of considerable interest. Magnetism has recently been implicated to play significant roles in the regulation of cell responses and, for this reason, it is revolutionizing many aspects of healthcare, also suggesting new opportunities in tissue engineering. The aim of the present study was to analyze the effect of the application mode of a time-dependent magnetic field on the behavior of human mesenchymal stem cells (hMSCs) seeded on 3D additive-manufactured poly(ɛ-caprolactone)/iron-doped hydroxyapatite (PCL/FeHA) nanocomposite scaffolds.
P09.15 Does a long term temozolomide have a favor effect on long surviving glioblastoma patients?
Authors: S. Ikuta, T. Maruyama
Journal: Neuro-Oncology (2017)

Chemotherapy with temozolomide (TMZ) and radiotherapy after tumor removal are still regarded as standard therapeutics for glioblastoma patients. After chemoradiotherapy (CRT), additional six cycles of TMZ is usually given, but it is unclear whether six cycles are sufficient to reduce recurrence. In our series, 25% of patients with GBM treated with TMZ lived more than one year without recurrence, and most of them received 12 cycles or more of TMZ chemotherapy. We retrospectively assessed the efficacy of long term TMZ in these case series. METHOD: Patients with newly diagnosed GBM, treated with 12 cycles or more TMZ after concomitant radiotherapy without relapse, were consecutively sampled at our institution from 2006 to 2014. The patents were categorized into 2 groups; the patents given 12 cycles of TMZ, and beyond 12 cycles. Progression free survival (PFS) and the overall survival (OS) after initial surgery were analyzed by Kaplan-Meier estimate. Results: A total of 52 patients met the criteria; 12 patients in the 12 cycles of TMZ group and 40 patients were in over 12 cycles of TMZ group. Median survival time (MST) and PFS of all patients was 6.8 and 4.1 years, respectively. There were no significant differences in PFS after the initial surgery between the 12 cycle group and the over 12 cycle groups (5.5 and 4.1 years respectively, p=0.3852). Also, OS showed no difference between the groups (5year survival; 70.7 and 63.7% respectively, p=0.8222), suggesting no benefit of more than 12 cycles of chemotherapy. CONCLUSION: This study suggested that patients with newly diagnosed GBM who are able to continue 12 cycles of TMZ chemotherapy can expect 6.3 years of OS and 4.1 years of PFS. More than 12 cycles of chemotherapy showed no additional survival benefit.
Rapid cell expansion (RACE) technology for production of engineered autologous T-cell therapy: Path toward manageable multicenter clinical trials in aggressive NHL with anti-CD19 CAR.
Authors: Marc Better, Omar Pugach, Lily Lu, Robert Somerville, Sadik Kassim, James Kochenderfer, Steven A. Rosenberg, Margaret A. Marshall, Adrian Bot, Keith B. Nolop, Margo Roberts, Steven Feldman
Journal: Journal of Clinical Oncology (2014)

3079 Background: Engineered autologous T cell therapy is proving to be a promising method to treat a variety of tumor types. An ongoing National Cancer Institute (NCI) Phase 1/2a study in patients with refractory B cell malignancies has been particularly encouraging, with data presented most recently at the ASH 2013 annual meeting. To prepare for Kite-sponsored multicenter trials, a rapid and compliant manufacturing process has been developed. Because refractory B cell malignancies can progress quickly, it is important to reduce the time between apheresis of patient PBMCs and administration of the engineered T cells. Methods: PBMCs from normal donors and patients with B cell malignancies were stimulated in vitro with anti-CD3 antibody in the presence of IL-2 to initiate T cell growth. The cells were then transduced with a gamma-retroviral vector containing an anti-CD19 CAR gene and propagated in culture to generate sufficient engineered T cells for administration. Results: We have developed a 6-day manufacturing process in serum-free media without the use of CD3/CD28 beads. Development studies have demonstrated in vitro analytical comparability to cells produced using an open system at the NCI. Conclusions: Kite in conjunction with the NCI Surgery Branch has developed a rapid and efficient proprietary process for the generation of anti-CD19 CAR cells. A Kite-sponsored multicenter clinical trial in patients with aggressive non-Hodgkin lymphoma using T cells generated by this new manufacturing process is expected to begin in early 2015.
Soluble Interleukin-2 Receptor and C-Reactive Protein Levels Are Associated with the Efficacy of Bendamustine As a Salvage Treatment for Indolent Lymphoma
Authors: Yukiko Kawaguchi, Bungo Saito, Maasa Abe, Yuta Baba, Sou Murai, Megumi Watanuki, Nana Arai, Shun Fujiwara, Nobuyuki Kabasawa, Hiroyuki Tsukamoto, Yui Uto, Kouji Yanagisawa, Norimichi Hattori, Tsuyoshi Nakamaki
Journal: Blood (2016)
CXCR5-Overexpressing Mesenchymal Stromal Cells Exhibit Enhanced Homing and Can Decrease Contact Hypersensitivity
Authors: Xiaoran Zhang, Weijun Huang, Xiaoyong Chen, Yufan Lian, Jiancheng Wang, Chuang Cai, Li Huang, Tao Wang, Jie Ren, Andy Peng Xiang
Journal: Molecular Therapy (2017)

Mesenchymal stromal cells (MSCs) can modulate inflammation and contribute to tissue regeneration and, thus, have emerged as a promising option for cell-based therapy. However, the ability of MSCs to migrate to injured tissues still needs to be improved. In this study, we investigated whether genetically engineered MSCs could exhibit increased migratory properties and improved therapeutic efficacy. Using a mouse model of contact hypersensitivity (CHS), chemokine gene expression screening revealed that CXCL13 changed most significantly in injured tissue. Unfortunately, MSCs hardly express the corresponding receptor, CXCR5. Thus, CXCR5-overexpressing MSCs (MSCCXCR5) were generated that retained their abilities of proliferation, differentiation, and immunomodulation. Furthermore, MSCCXCR5 showed significantly increased migrating ability toward CXCL13. Importantly, systemic infusion of MSCCXCR5 dramatically suppressed CHS in mice, as evidenced by decreased levels of inflammatory cell infiltration and pro-inflammatory cytokine production. Numerous MSCCXCR5 migrated into inflamed ears, localized with T cells, inhibited T cell proliferation, promoted T cell apoptosis, and suppressed the production of T cell-derived pro-inflammatory factors. Collectively, these findings demonstrate that CXCR5 overexpression increases the ability of MSCs to respond to migratory stimuli and highly intensifies their immunomodulatory effects in vivo. This strategy for enhancing targeted stem/progenitor cell homing may improve the efficacy of MSC-based therapies.
Abstract 261: Foxo4 Promotes Early Inflammatory Response Upon Myocardial Infarction via Endothelial Arg1
Authors: Min Zhu, Zhaoning Wang, Robert Luo, Sean Goetsch, Jay Schneider, Joseph Hill, Sidney Morris Jr., Zhi-Ping Liu
Journal: Circulation Research (2015)

Myocardial infarction (MI) can result in a maladaptive remodeling of the heart that leads to heart failure. The post-MI inflammation is necessary for wound healing. Unfortunately it is also a key component of subsequent heart failure pathology. Thus, understanding the mechanism of post-MI inflammation and identifying targets for intervention are of translational interests. To understand the role of FoxO4 in post-MI remodeling, we induced MI in WT and FoxO4 global knockout ( gKO ) mice by surgical ligation of the left anterior descending coronary artery. FoxO4- inactivation resulted in a significantly higher post-MI survival, better cardiac function, and reduced fibrosis and infarct size compared to WT mice. FoxO4 gKO mouse hearts had significantly less mount of neutrophils, and reduced expressions of cytokines, MMP9, and Arginase 1 (Arg1). To determine the contribution of cellular FoxO4 to the post-MI phenotype, we generated cardiomyocyte and endothelial cell specific FoxO4 knockout mice ( FoxO4 cKO and eKO ). While FoxO4 cKO mice showed similar post-MI phenotype to those of WT littermates, FoxO4 eKO mice had better cardiac function with reduced inflammation, neutrophil infiltration, and Arg1 expression similar to those of FoxO4 gKO mice. Since Arg1 is a competitive inhibitor of nitric oxide (NO) synthase and NO inhibits lymphocyte adhesion and transmigration across the endothelial barrier, downregulation of neutrophils in post-MI FoxO4- null mouse hearts could be due to reduced endothelial Arg1 and thus increased NO. Consistent with this hypothesis, we show that Arg1 is a direct transcriptional target of FoxO4. Endothelial FoxO4 is necessary and sufficient to activate Arg1 expression in response to hypoxia. Knockdown of FoxO4 in human aortic endothelial cells suppressed leukocyte adhesion. Furthermore, chemical inhibition of Arg1 in WT mice had similar cardioprotection following MI as FoxO4- inactivation and administration of NOS inhibitor to FoxO4 gKO mice reversed the beneficial effects of FoxO4 -deletion on post-MI cardiac function. Our studies showed that FoxO4 promotes early inflammatory response via endothelial Arg1 and suggest a potential therapy to reduce the early post-MI inflammation and enhance cardiac function in MI-injured hearts.
Skin manifestations among<i>GATA2</i>-deficient patients
Authors: A. Polat, M. Dinulescu, S. Fraitag, S. Nimubona, F. Toutain, S. Jouneau, E. Poullot, C. Droitcourt, A. Dupuy
Journal: British Journal of Dermatology (2017)

GATA2 mutations have been identified in various diseases, such as MonoMAC syndrome, Emberger syndrome, familial myelodysplastic syndrome, acute myeloid leukaemia and dendritic cell, monocyte, B‐cell and natural killer‐cell deficiency. These syndromes present a wide range of clinical features, dominated by severe infections and haematological disorders such as myelodysplastic syndrome. Up to 70% of patients with GATA2 mutations have dermatological features, mainly genital or extragenital warts, panniculitis or erythema nodosum and lymphoedema. We report three patients presenting with common dermatological and haematological features leading to the diagnosis of GATA2 deficiency, but also with skin manifestations that have not been previously described: gingival hypertrophy, macroglossitis and glossitis and granulomatous lupoid facial lesions. Dermatologists can encounter patients with GATA2 mutations and should recognize this disorder.
Arginine‐Rich Peptide‐Based mRNA Nanocomplexes Efficiently Instigate Cytotoxic T Cell Immunity Dependent on the Amphipathic Organization of the Peptide
Authors: Vimal K. Udhayakumar, Ans De Beuckelaer, Joanne McCaffrey, Cian M. McCrudden, Jonathan L. Kirschman, Daryll Vanover, Lien Van Hoecke, Kenny Roose, Kim Deswarte, Bruno G. De Geest, Stefan Lienenklaus, Philip J. Santangelo, Johan Grooten, Helen O. McCarthy, Stefaan De Koker
Journal: Advanced Healthcare Materials (2017)

To date, the mRNA delivery field has been heavily dominated by lipid-based systems. Reports on the use of nonlipid carriers for mRNA delivery in contrast are rare in the context of mRNA vaccination. This paper describes the potential of a cell-penetrating peptide containing the amphipathic RALA motif to deliver antigen-encoding mRNA to the immune system. RALA condenses mRNA into nanocomplexes that display acidic pH-dependent membrane disruptive properties. RALA mRNA nanocomplexes enable mRNA escape from endosomes and thereby allow expression of mRNA inside the dendritic cell cytosol. Strikingly, RALA mRNA nanocomplexes containing pseudouridine and 5-methylcytidine modified mRNA elicit potent cytolytic T cell responses against the antigenic mRNA cargo and show superior efficacy in doing so when compared to RALA mRNA nanocomplexes containing unmodified mRNA. RALA's unique sequence and structural organization are vital to act as mRNA vaccine vehicle, as arginine-rich peptide variants that lack the RALA motif show reduced mRNA complexation, impaired cellular uptake and lose the ability to transfect dendritic cells in vitro and to evoke T cell immunity in vivo.
Melanocortin 1 Receptor Signaling Regulates Cholesterol Transport in Macrophages
Authors: Petteri Rinne, Martina Rami, Salla Nuutinen, Donato Santovito, Emiel P.C. van der Vorst, Raquel Guillamat-Prats, Leo-Pekka Lyytikäinen, Emma Raitoharju, Niku Oksala, Larisa Ring, Minying Cai, Victor J. Hruby, Terho Lehtimäki, Christian Weber, Sabine Steffens
Journal: Circulation (2017)

Background: The melanocortin 1 receptor (MC1-R) is expressed by monocytes and macrophages, where it exerts anti-inflammatory actions on stimulation with its natural ligand α-melanocyte–stimulating hormone. The present study was designed to investigate the specific role of MC1-R in the context of atherosclerosis and possible regulatory pathways of MC1-R beyond anti-inflammation. Methods: Human and mouse atherosclerotic samples and primary mouse macrophages were used to study the regulatory functions of MC1-R. The impact of pharmacological MC1-R activation on atherosclerosis was assessed in apolipoprotein E–deficient mice. Results: Characterization of human and mouse atherosclerotic plaques revealed that MC1-R expression localizes in lesional macrophages and is significantly associated with the ATP-binding cassette transporters ABCA1 and ABCG1, which are responsible for initiating reverse cholesterol transport. Using bone marrow–derived macrophages, we observed that α-melanocyte–stimulating hormone and selective MC1-R agonists similarly promoted cholesterol efflux, which is a counterregulatory mechanism against foam cell formation. Mechanistically, MC1-R activation upregulated the levels of ABCA1 and ABCG1. These effects were accompanied by a reduction in cell surface CD36 expression and in cholesterol uptake, further protecting macrophages from excessive lipid accumulation. Conversely, macrophages deficient in functional MC1-R displayed a phenotype with impaired efflux and enhanced uptake of cholesterol. Pharmacological targeting of MC1-R in atherosclerotic apolipoprotein E–deficient mice reduced plasma cholesterol levels and aortic CD36 expression and increased plaque ABCG1 expression and signs of plaque stability. Conclusions: Our findings identify a novel role for MC1-R in macrophage cholesterol transport. Activation of MC1-R confers protection against macrophage foam cell formation through a dual mechanism: It prevents cholesterol uptake while concomitantly promoting ABCA1- and ABCG1-mediated reverse cholesterol transport.