tbuckley/cabot-search huggingface dataset:
IMMU-17. TRANSGENIC EXPRESSION OF IL15 IMPROVES ANTIGLIOMA ACTIVITY OF IL13RΑ2-CAR T CELLS
Authors: David Steffin, Brooke Prinzing, Zhongzhen Yi, Irina Balyasnikova, Gianpietro Dotti, Stephen Gottschalk, Giedre Krenciute
Journal: Neuro-Oncology (2017)

The goal of this project is to develop T-cells expressing IL13Rα2-specific chimeric antigen receptor (CAR) as an effective immunotherapy for diffuse intrinsic pontine glioma (DIPG) and glioblastoma (GBM), the most aggressive, highly lethal, primary human brain tumors in children. We recently demonstrated that IL13Rα2-CARs with a CD28.ζ endodomain had potent anti-GBM activity in preclinical models. However, IL13Rα2-CAR T-cell persistence was limited, resulting in recurrence of IL13Rα2-positive GBMs. Next we wanted to evaluate if transgenic expression of IL15 enhances persistence and anti-tumor activity of IL13Rα2-CAR.CD28.ζ T-cells. We generated IL13Rα2-CAR.CD28.ζ T-cells expressing IL-15 (IL13Rα2-CAR.IL15 T cells) and determined the effector function of IL13Rα2-CAR.IL15 T cells in vitro and in vivo. Double transduction of CD3/CD28-activated T cells resulted in T-cell lines that expressed both transgenes in 45–50% of T cells. At base line IL13Rα2-CAR.IL15 T cells produced on average 69.5 pg/ml of IL15. Production was significantly increased after CD3 or antigen-specific T-cell stimulation (176.7 pg/ml; n=6; p<0.001). IL13Rα2-CAR.IL15 T-cells were as efficient as IL13Rα2-CAR T-cells in killing IL13Rα2-positive GBMs in vitro. After intratumoral injection into U373 glioma-bearing mice IL13Rα2-CAR.IL15 T cells persisted significantly longer than IL13Rα2-CAR T cells (p<0.05). This resulted in a significant increase in progression free (84 vs 49 days; p=0.008) and overall survival (p=0.02) of treated mice. 3/5 examined, recurring U373 gliomas post IL13Rα2-CAR.IL15 T-cell therapy had down regulated IL13Rα2 expression, indicating immune escape. While all recurring GBMs expressed the glioma-associated antigen EphA2, 1/5 GBMs had also down regulated the expression of the glioma-associated antigen HER2. In conclusion, transgenic expression of IL15 enhances the in vivo persistence of IL13Rα2-CAR T cells resulting in improved anti-glioma activity. However, enhanced in vivo T-cell persistence resulted in the development of antigen-specific and -unspecific loss variants highlighting the need to target multiple glioma-associated antigens in tumors with heterogeneous antigen expression such as GBM.
Limited engraftment of donor microbiome via one-time fecal microbial transplantation in treated HIV-infected individuals
Authors: Ivan Vujkovic-Cvijin, Rachel L. Rutishauser, Montha Pao, Peter W. Hunt, Susan V. Lynch, Joseph M. McCune, Ma Somsouk
Journal: Gut Microbes (2017)

Many HIV-infected individuals on antiretroviral therapy (ART) exhibit persistent systemic inflammation, which predicts morbidity and mortality. ART-treated subjects concurrently exhibit marked compositional alterations in the gut bacterial microbiota and the degree of dysbiosis correlates with systemic inflammation. Whether interventions to modulate the microbiome can affect systemic inflammation is unknown. An open-label fecal microbial transplantation (FMT) was delivered by colonoscopy to asymptomatic HIV-infected ART-suppressed individuals without antibiotic pre-treatment. Stool was assessed before and after FMT for engraftment of donor microbes, and peripheral blood was assayed for immune activation biomarkers. Six participants received FMT and 2 participants served as controls. No serious adverse effects occurred during 24 weeks of follow-up. At baseline, HIV-infected individuals exhibited microbiota profiles distinct from uninfected donors. During the 8 weeks post-FMT, recipients demonstrated partial engraftment of the donor microbiome (P < 0.05). Recipient microbiota remained significantly distant from donors, unlike that observed following FMT for treatment of C. difficile infection. Systemic inflammatory markers showed no significant change post-FMT. FMT was well-tolerated in ART-treated, HIV-infected individuals. Engraftment was detectable but modest, and appeared to be limited to specific bacterial taxa. Whether antibiotic conditioning can enhance engraftment and the capacity of microbiota to modulate inflammation remains to be investigated.
Role of medical resource level in iodine deficiency disorder
Authors: Chen Xu, Zhen Liang, Yong-Jun Luo
Journal: Military Medical Research (2017)

Iodine deficiency disorders (IDDs) refer to a series of diseases caused by the human body's insufficient iodine intake. Edible salt became iodized in China in 1996, which yielded remarkable results. We have known that IDDs is associated with iodine in the human body, but it is not clear whether IDDs is related to medical resource level. We collected the number of IDDs cases and an index for the level of medical resource from 31 provinces, autonomous regions and municipalities directly under the central government in China. All data came from the China Statistical Yearbook of Health and Family Planning issued in 2013 by the Peking Union Medical College Publishing House. Data standardization and linear regression analysis were used. The results showed that IDDs correlated with the number of beds in medical and health institutions, number of medical health personnel, number of medical and health institutions, total health expenditure, average health expenditure per capita, medical insurance for urban resident and new rural cooperative medical rural residents (P < 0.01). In a multiple linear regression, IDDs was most significantly associated with the number of beds in hospitals, the number of rural health personnel, the number of basic medical and health institutions and government health expenditure for these institutions. Based on the experimental data, we concluded that IDDs had a positive connection with the medical resource level, and basic and rural areas had a more significant association with IDDs. This analysis provides new and explicit ideas for iodine prevention and control work in China.
MEDU-08. INCIDENCE OF POSTERIOR FOSSA SYNDROME IN CHILDREN AT A TERTIARY CARE HOSPITAL IN KARACHI
Authors: Naureen Mushtaq, Sadia Usman
Journal: Neuro-Oncology (2017)

OBJECTIVE: Pediatric brain tumors accounts for 25% of all cancers, out of which 60% arises in posterior fossa.The most debilitating complication of posterior fossa surgery is Posterior fossa syndrome (PFS) or Cerebellar mutism syndrome. The overall incidence of PFS is 11–29%. It is characterized by mutism/reduced speech, ataxia, dysphagia, long tract signs, cranial nerves neuropathies, cognitive, and neurobehavioral abnormalities. The incidence of this serious neurosurgical complication remains incompletely defined in developing countries. This study aims to determine the incidence of PFS in children for early anticipation and prevention of PFS. METHODS/MATERIALS: All children (<1year-18years) with posterior fossa tumor undergone surgical resection from January 2014-December 2016 at Aga Khan University Hospital were reviewed retrospectively for symptoms, radiological findings, histopathology and management of posterior fossa syndrome. Children previously diagnosed with neurological impairment or syndromic/genetic conditions affecting brain or those who were only biopsied were excluded. RESULTS: 32 patients were included in our study. The median age was 3 years. Male to female ratio is M:F (4.3:1). PFS developed in 26(81%) patients, most commonly with medulloblastoma 17(53%). Most common site was 4th ventricle 18(56.3%).Most of the tumors were grossly resected 19(59%).Most common symptoms were irritability 25(78%), emotional labiality 25(78%), followed by ataxia 23(72%), impaired hand writing 20(62%) and slurred speech 19(60%). Steroids were given to all patients pre and post operatively. 26(81%) patients were undergone aggressive physiotherapy and 12(37%) received zolpidem for improvement in symptoms. CONCLUSION: This is the only study about posterior fossa syndrome from Pakistan and it depicted that majority of our patients undergone posterior fossa tumor resection experienced PFS as compared to the data from developed world. It is a post-surgical complication therefore safe surgical resection, early anticipation of complication and timely management strategies should be sought out as early as possible by a collaborative team effort.
DIPG-40. PNOC-003: PRECISION MEDICINE TRIAL FOR CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Sabine Mueller, Winnie Liang, Nalin Gupta, Suresh Magge, Lindsay Kilburn, John Crawford, Anu Banerjee, Kellie Nazemi, Roger Packer, Claudia Petritsch, Nathalene Truffaux, Alison Roos, Theodore Nicolaides, David Craig, John Carpten, Sara Byron, John Kuhn, Adam Resnick, Michael Berens, Michael Prados, Javad Nazarian
Journal: Neuro-Oncology (2017)
A safety evaluation of profound hypothermia-induced suspended animation for delayed resuscitation at 90 or 120 min
Authors: Yu Liu, Shu Li, Zhi Li, Jian Zhang, Jin-song Han, Yong Zhang, Zong-tao Yin, Hui-shan Wang
Journal: Military Medical Research (2017)

The successful treatment of military combat casualties with penetrating injuries is significantly dependent on the time needed to get the patient to an adequate treatment facility. Profound hypothermia-induced suspended animation for delayed resuscitation (SADR) is a novel approach for inducing cardiac arrest and buying additional time for such injuries. However, the time used to safely administer circulatory arrest (CA) is controversial. The goal of this study was to evaluate the safety of hypothermia-induced SADR over 90 and 120 min time intervals. Sixteen male BAMA minipigs were randomized into two groups: CA90 group (90 min, n = 8) and CA120 group (120 min, n = 8). Cannulation of the right common carotid arteries and internal jugular veins was performed to establish cardiopulmonary bypass for each animal. Through the perfusion of cold organ preservation solution (OPS), cardioplegia and profound hypothermia (15 °C) were induced. After CA, cardiopumonary bypass (CPB) was restarted, and the animals were gradually re-warmed and resuscitated. The animals were assisted with ventilators until spontaneous breathing was achieved. The index of hemodynamic perioperative serum chemistry values [alanine transaminase (ALT), aspartate aminotransferase (AST), creatinine (CR), lactic dehydrogenase (LDH) and troponin T (TnT)] and survival were observed from pre-operation to 7 days post-operation. Fifteen animals were enrolled in the experiment, while 1 animal in CA120 group died from surgical error. All 8 animals in CA90 group recovered, with only 1 animal displaying mild disability. However, in CA120 group, only 2 animals survived with severe disability, and the other 5 animals died after 2 days post-operation. In CA90 group, the perioperative serum chemistry values increased at 1 day post-operation (ALT 84.43 ± 18.65 U/L; AST 88.99 ± 23.19 U/L; Cr 87.90 ± 24.49 μmol/L; LDH 1894.13 ± 322.26 U/L; TnT 0.849 ± 0.135 ng/ml) but decreased to normal or almost normal levels at 7 days post-operation (ALT 52.48 ± 9.04 U/L; AST 75.23 ± 21.46 U/L; Cr 82.69 ± 18.41 μmol/L; LDH 944.67 ± 834.32 U/L; TnT 0.336 ± 0.076 ng/ml). Profound hypothermia-induced SADR is an effective method for inducing cardiac arrest. Our results indicate that inducing CA for 90 min (at 15 °C) is safer than doing so for 120 min. Our results indicate that 120 min of CA at 15 °C is dangerous and can result in high mortality and severe neurological complications. Further experimentation is needed to determine whether 120 min of CA at temperatures lower than 15 °C can lead to safe recovery.
BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency
Authors: Behdad Afzali, Juha Grönholm, Jana Vandrovcova, Charlotte O'Brien, Hong-Wei Sun, Ine Vanderleyden, Fred P Davis, Ahmad Khoder, Yu Zhang, Ahmed N Hegazy, Alejandro V Villarino, Ira W Palmer, Joshua Kaufman, Norman R Watts, Majid Kazemian, Olena Kamenyeva, Julia Keith, Anwar Sayed, Dalia Kasperaviciute, Michael Mueller, Jason D Hughes, Ivan J Fuss, Mohammed F Sadiyah, Kim Montgomery-Recht, Joshua McElwee, Nicholas P Restifo, Warren Strober, Michelle A Linterman, Paul T Wingfield, Holm H Uhlig, Rahul Roychoudhuri, Timothy J Aitman, Peter Kelleher, Michael J Lenardo, John J O'Shea, Nichola Cooper, Arian D J Laurence
Journal: Nature Immunology (2017)
Sixty seconds on . . . purdah
Authors: Anne Gulland
Journal: BMJ (2017)

No, of course not. I mean the pre-election period when no new policy announcements can be made, and civil servants cannot provide support to ministers working on the election campaign. However, during this election there have been grumblings that the government is taking purdah too far.

In a letter to the cabinet secretary, Jeremy Heywood, the Science Media Centre and other organisations such as the Royal Statistical Society and the Royal Institution said that scientific researchers have felt unable to comment on certain news …
Preventing Nocebo Effects of Informed Consent Without Paternalism
Authors: Shlomo Cohen
Journal: The American Journal of Bioethics (2017)

In their article “When Respecting Autonomy is Harmful: A Clinically Useful Approach to the Nocebo Effect,” (2017) John Fortunato and colleagues (Fortunato, Wasserman, and Menkes 2017) argue for the...
Modulating the phenotype of host macrophages to enhance osteogenesis in MSC-laden hydrogels: Design of a glucomannan coating material
Authors: Yiming Niu, Qiu Li, Ruiyu Xie, Shang Liu, Ruibing Wang, Panfei Xing, Yuchen Shi, Yitao Wang, Lei Dong, Chunming Wang
Journal: Biomaterials (2017)
The role of GSK3β in rapamycin-mediated cell cycle regulation
Authors: Jinjiang Dong, Junying Peng, Haixia Zhang, Wallace H. Mondesire, Weiguo Jian, Gordon B. Mills, Mien-Chie Hung, Funda Meric-Bernstam
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

1506 

The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that regulates cell cycle progression. Rapamycin and its analogues inhibit mTOR and are being actively investigated in clinical trials as novel targeted anticancer agents. Although cyclin D1 is downregulated by rapamycin, the role of this downregulation in rapamycin-mediated growth inhibition and the mechanism of cyclin D1 downregulation are not well understood. Here we show that overexpression of cyclin D1 partially overcomes rapamycin-induced cell cycle arrest and inhibition of anchorage-dependent growth in breast cancer cells. Rapamycin not only decreases endogenous cyclin D1 levels, but also decreases the expression of transfected cyclin D1, suggesting that this is at least in part caused by accelerated proteolysis. Indeed, rapamycin decreases the half-life of cyclin D1 protein, and the rapamycin-induced decrease in cyclin D1 levels is partially abrogated by proteosome inhibitor N -acetyl-leucyl-leucyl-norleucinal. Rapamycin treatment leads to an increase in the kinase activity of glycogen synthase kinase3β (GSK3β), a known regulator of cyclin D1 proteolysis. Rapamycin-induced downregulation of cyclin D1 is inhibited by GSK3β inhibitors lithium chloride (LiCl), SB216763 and SB415286. Rapamycin-induced G1 arrest is abrogated by nonspecific GSK3β inhibitor LiCl, but not by selective inhibitor SB216763; thus GSK3β is not essential for rapamycin-mediated G1 arrest. However, rapamycin inhibits cell growth significantly more in GSK3β wild-type cells than in GSK3β-null cells, suggesting that GSK3β significantly enhances rapamycin-mediated growth inhibition. Taken together, these results demonstrate that GSK3β plays an important role in rapamycin-mediated cell cycle regulation and growth inhibition.
Metabolomic biomarkers of concussion
Authors: Eric James Paxman, Zachary Wanner, Jyote Boora, Kiss Douglas, Gerlinde Metz, Tony Montina, Chantel Debert
Journal: British Journal of Sports Medicine (2017)

Objective To determine if 1 H NMR spectroscopy of urine and a quantitative metabolomics approach can aid diagnostic and prognostic outcomes in patients who have suffered acute sport concussion. Design Pre-concussion urine samples were collected from WinSport athletes at the beginning of the sport season. Any athlete who experienced a head injury reported to a brain injury clinic to be tested within 72 hours of head injury. This testing included collection of a post-concussion urine sample for metabolomic analysis. Setting Brain injury clinic and metabolomics laboratory. Participants 167 athletes entered the study with a total of 39 concussions occurring. Inclusion criteria: at least 18 years old, diagnosis of concussion, and concussion sustained within 72 hours. Exclusion criteria: multiple injuries coinciding with concussion and a past history of neurological pathology. Outcome measures Metabolite concentrations were calculated in pre- and post-concussion urine samples and compared using a paired t-test and partial least squares discriminant analysis (PLS-DA) to determine which metabolites led to significant variation between samples. Main results The PLS-DA model showed significant variation between baseline and post-injury sample groups and passed all permutation and cross-validation testing. A paired t-test, with cross-validation, isolated five significant metabolites of interest in the concussion group (p&lt;0.05). Conclusions Using NMR spectroscopy we quantified urinary metabolites in patients before and after concussion. This revealed several metabolites that were shown to be significantly altered following injury, opening up future inquiry into both the pathways and processes involved in concussion and new avenues for personalized diagnosis and treatment. Competing interests None.
Abstract 213: Deletion of 12/15 Lipoxygenase and Fatty Acids Interaction Alters Leukocyte Kinetics Leading to Improved Healing Following Myocardial Infarction
Authors: Ganesh V Halade, Vasundhara Kain, Kevin A Ingle, Janusz H Kabarowski, Stephen Barnes, Sumanth D Prabhu
Journal: Circulation Research (2015)

The 12/15 lipoxygenase (LOX) enzyme catalyzes oxygenation of fatty acids to form lipid mediators leading to non-resolving inflammation. However, how 12/15LOX interacts with PUFA (polyunsaturated fatty acids) in post-myocardial infarction (MI) cardiac healing is unclear. Here we assessed the role of 12/15LOX in post-MI cardiac remodeling in a PUFA (10% w/w, 22 Kcal) enriched environment. C57BL/6J wild-type (WT) and 12/15LOX null (12/15LOX –/– ) male mice of 8-12-weeks age were fed PUFA-enriched diet for 1 month and subjected to permanent coronary artery ligation. Post-MI mice were monitored for day (d)1 or d5 along with standard diet (SD)-fed MI controls. No-MI surgery mice served as d0 controls. 12/15LOX and PUFA+12/15LOX -/- mice reduced infarcted wall thinning with decreased lung edema index at d5 post-MI (all p&lt;0.05) despite comparable infarct area (49-52%). PUFA+WT and 12/15LOX -/- mice showed improved ejection fraction with reduced left ventricle (LV) hypertrophy index than SD+WT at d5 post-MI (p&lt;0.05). The neutrophil density was decreased in both PUFA+WT and 12/15LOX -/- mice at d1 post-MI (P&lt;0.05). The neutrophil clearance was rapid in 12/15LOX -/- alone and PUFA+12/15LOX -/- mice, with increases in expression of formyl peptide receptor 2 at d5 post-MI. The macrophage density was decreased in PUFA+WT and 12/15LOX -/- mice compared with their respective SD+WT control at d5 post-MI. PUFA+12/15LOX -/- mice displayed an increased expression of ccl2 (all p&lt;0.05) in the infarct area. 12/15LOX deletion stimulated 5-LOX and heme oxygenase-1 in PUFA+12/15LOX -/- mice with increased levels of 9-and 13-hydroxyoctadecadienoic acid indicating improved resolution of inflammation at d5 post-MI. The PUFA+12/15LOX -/- mice displayed higher expression of proresolving macrophages ym-1, mrc-1 and arg-1 compared with SD+12/15LOX -/- mice at d5 post-MI (all p&lt;0.05). Further, 12/15LOX -/- mice with or without PUFA showed reduced collagen deposition at d5 post-MI compared to SD+WT. In conclusion, deletion of 12/15LOX and short-term PUFA exposure attenuated cardiac remodeling via shortening the pro-inflammatory window, thus leading to an improved resolution of inflammation and LV function post-MI.
C10ORF10/DEPP-mediated ROS accumulation is a critical modulator of FOXO3-induced autophagy
Authors: S. Salcher, M. Hermann, U. Kiechl-Kohlendorfer, M. J. Ausserlechner, P. Obexer
Journal: Molecular Cancer (2017)

Neuroblastoma is the most common solid tumor in childhood and develops from undifferentiated progenitor cells of the sympathetic nervous system. In neuronal tumor cells DNA-damaging chemotherapeutic agents activate the transcription factor FOXO3 which regulates the formation of reactive oxygen species (ROS) and cell death as well as a longevity program associated with therapy resistance. We demonstrated before that C10ORF10/DEPP, a transcriptional target of FOXO3, localizes to peroxisomes and mitochondria and impairs cellular ROS detoxification. In the present study, we investigated the impact of FOXO3 and DEPP on the regulation of autophagy. Autophagy serves to reduce oxidative damage as it triggers a self-degradative process for the removal of aggregated or misfolded proteins and damaged organelles.The effect of FOXO3 and DEPP on autophagy induction was analyzed using live cell fluorescence microscopy and immunoblot analyses of SH-EP cells transfected with a plasmid for EYFP-LC3 and with siRNAs specific for LC3, respectively. ROS steady-state levels were measured with reduced MitoTrackerRed CM-H2XROS. Cellular apoptosis was analyzed by flow cytometry and the caspase 3/7 assay.We report for the first time that DEPP induces ROS accumulation and thereby mediates the formation of autophagosomes as inhibition of ROS formation by N-acetyl-cysteine completely blocks autophagy. We further demonstrate that H2O2-treatment triggers autophagy-induction by FOXO3-mediated DEPP expression. Importantly, knockdown of DEPP was sufficient to efficiently inhibit autophagy-induction under different stress conditions such as serum starvation and genotoxic stress, suggesting that DEPP expression is critical for the initiation of autophagy in neuroblastoma. FOXO3-triggered autophagy partially protects neuroblastoma cells from cell death. Consistent with this concept, we demonstrate that inhibition of autophagy by LC3-knockdown significantly increased etoposide- and doxorubicin-induced apoptosis. These results were also confirmed by the use of the autophagy-inhibitor chloroquine that significantly enhanced the chemotherapeutic effect of etoposide and doxorubicin in neuronal tumor cells.Targeting FOXO3/DEPP-triggered autophagy is a promising strategy to sensitize neuroblastoma cells to chemotherapy.