tbuckley/cabot-search huggingface dataset:
Carbon ion radiotherapy boost in the treatment of glioblastoma: a randomized phase I/III clinical trial
Authors: Lin Kong, Jing Gao, Jiyi Hu, Rong Lu, Jing Yang, Xianxin Qiu, Weixu Hu, Jiade J. Lu
Journal: Cancer Communications (2019)

Abstract Background Glioblastoma (GBM) is a highly virulent tumor of the central nervous system, with a median survival &lt; 15 months. Clearly, an improvement in treatment outcomes is needed. However, the emergence of these malignancies within the delicate brain parenchyma and their infiltrative growth pattern severely limit the use of aggressive local therapies. The particle therapy represents a new promising therapeutic approach to circumvent these prohibitive conditions with improved treatment efficacy. Methods and design Patients with newly diagnosed malignant gliomas will have their tumor tissue samples submitted for the analysis of the status of O‐6‐methylguanine‐DNA methyltransferase ( MGMT ) promoter methylation. In Phase I, the patients will undergo an induction carbon ion radiotherapy (CIRT) boost followed by 60 GyE of proton irradiation with concurrent temozolomide (TMZ) at 75 mg/m 2 . To determine the maximal dose of safe induction boost, the tolerance, and acute toxicity rates in a dose‐escalation manner from 9 to 18 GyE in three fractions will be used. In Phase III, GBM‐only patients will be randomized to receive either 60 GyE (2 GyE per fraction) of proton irradiation with concurrent TMZ (control arm) or a CIRT boost (dose determined in Phase I of this trial) followed by 60 GyE of proton irradiation with concurrent TMZ. The primary endpoints are overall survival (OS) and toxicity rates (acute and long‐term). Secondary endpoints are progression‐free survival (PFS), and tumor response (based upon assessment with C‐methionine/fluoro‐ethyl‐tyrosine positron emission tomography [MET/FET PET] or magnetic resonance imaging [MRI] and detection of serologic immune markers). We hypothesize that the induction CIRT boost will result in a greater initial tumor‐killing ability and prime the tumor microenvironment for enhanced immunologic tumor clearance, resulting in an expected 33% improvement in OS rates. Discussion The prognosis of GBM remains grim. The mechanism underpinning the poor prognosis of this malignancy is its chronic state of tumor hypoxia, which promotes both immunosuppression/immunologic evasion and radio‐resistance. The unique physical and biological properties of CIRT are expected to overcome these microenvironmental limitations to confer an improved tumor‐killing ability and anti‐tumor immune response, which could result in an improvement in OS with minimal toxicity. Trial registration number This trial has been registered with the China Clinical Trials Registry, and was allocated the number ChiCTR‐OID‐17013702.
Beyond sports: Efficacy and safety of creatine supplementation in pathological or paraphysiological conditions of brain and muscle
Authors: Maurizio Balestrino, Enrico Adriano
Journal: Medicinal Research Reviews (2019)

Abstract Creatine is pivotal in energy metabolism of muscle and brain cells, both in physiological and in pathological conditions. Additionally, creatine facilitates the differentiation of muscle and neuronal cells. Evidence of effectiveness of creatine supplementation in improving several clinical conditions is now substantial, and we review it in this paper. In hereditary diseases where its synthesis is impaired, creatine has a disease‐modifying capacity, especially when started soon after birth. Strong evidence, including a Cochrane meta‐analysis, shows that it improves muscular strength and general well‐being in muscular dystrophies. Significant evidence exists also of its effectiveness in secondary prevention of statin myopathy and of treatment‐resistant depression in women. Vegetarians and vegans do not consume any dietary creatine and must synthesize all they need, spending most of their methylation capacity. Nevertheless, they have a lower muscular concentration of creatine. Creatine supplementation has proved effective in increasing muscular and neuropsychological performance in vegetarians or vegans and should, therefore, be recommended especially in those of them who are athletes, heavy‐duty laborers or who undergo intense mental effort. Convincing evidence also exists of creatine effectiveness in muscular atrophy and sarcopenia in the elderly, and in brain energy shortage (mental fatigue, sleep deprivation, environmental hypoxia as in mountain climbing, and advanced age). Furthermore, we review more randomized, placebo‐controlled trials showing that creatine supplementation is safe up to 20 g/d, with a possible caveat only in people with kidney disease. We trust that the evidence we review will be translated into clinical practice and will spur more research on these subjects.
Abstract 289: Effect of Elevated Legs on Hemodynamic Performance During Cardiopulmonary Resuscitation in a Porcine Model of Cardiac Arrest
Authors: Eric Qvigstad, Andres Neset, Theresa M Olasveengen, øystein Tømte, Morten Eriksen, Per Andreas Norseng, Kjetil Sunde, Jo Kramer-Johansen
Journal: Circulation (2014)

Purpose of the study: During advanced life support (ALS) end-tidal carbon dioxide (EtCO 2 ) reflects cardiac output (CO). A recent clinical study found an association between passive leg raising (PLR) and increased EtCO 2 during ALS. This may reflect a transient increase in pulmonary blood flow and CO, but might cause a detrimental decrease in coronary perfusion pressure (CPP). We evaluated the effect of PLR during experimental ALS in a randomized, factorial design. Materials and methods: In nine anesthetized domestic pigs (30±1.8 kg) ventricular fibrillation was induced electrically. After 3 minutes of no-flow, mechanical chest compressions (5cm @ 100 min -1 ) were started. During four 5-minute segments of CPR we measured CO, EtCO 2 , perfusion pressures, carotid and cerebral cortical microcirculatory blood flow (MBF) and CPP (the average of the positive pressure difference between decompression aortic pressure (AP) and right atrial pressure (RAP)) at minute 2 and 4. Interventions were provided in a randomized sequence with PLR vs supine position, with or without epinephrine (0.5mg iv). Values are given as mean±standard deviation. Results: PLR did not increase EtCO2 compared to supine position (3.1±0.7 vs 3.0±0.8 kPa), but CO was minimally increased from 1.1±0.3 to 1.2±0.3 Lmin -1 ,(p=0.003). PLR did not significantly increase AP (57±15 vs. 48±18 mmHg, p=0.3), but RAP was higher (43±10 vs. 31±7, p=0.003). However, no difference was found in CPP due to marked variation in both groups (median(range): PLR 20 (9,43) and supine 17(9,58)). The effect of epinephrine during this experimental setup was minimal. Conclusion: We did not find a positive effect of PLR during experimental ALS, but there were no obviously detrimental effects either.
Studies of keratinocyte-specific regulatory interactions by three-dimensional mapping with a focus on atopic dermatitis
Authors: I. Tapia-Paez, S. Asad, F. Taylan, Rapolas Spalinskas, A. Anandashankar, M. Nordenskjold, C. F. Wahlgren, Pelin Sahlén, M. Bradley
Journal: British Journal of Dermatology (2018)

Studies of keratinocyte-specific regulatory interactions by three-dimensional mapping with a focus on atopic dermatitis
Prediction of Sudden Cardiac Death in Implantable Cardioverter Defibrillators: A Review and Comparative Study of Heart Rate Variability Features
Authors: Ashkan Parsi, Declan O'Loughlin, Martin Glavin, Edward Jones
Journal: IEEE Reviews in Biomedical Engineering (2019)

Over the last four decades, implantable cardioverter defibrillators (ICDs) have been widely deployed to reduce sudden cardiac death (SCD) risk in patients with a history of life-threatening arrhythmia. By continuous monitoring of the heart rate, ICDs can use decision algorithms to distinguish normal cardiac sinus rhythm or supra-ventricular tachycardia from abnormal cardiac rhythms like ventricular tachycardia and ventricular fibrillation and deliver appropriate therapy such as an electrical stimulus. Despite the success of ICDs, more research is still needed, particularly in decision-making algorithms. Because of low specificity in practical devices, patients with ICDs still receive inappropriate shocks, which may lead to inadvertent mortality and reduction of quality of life. At the same time, higher sensitivity can lead to the use of newer tiered therapies. The purpose of this study is to review the literature on common signal features used in detection algorithms for abnormal cardiac sinus rhythm, as well as reviewing datasets used for algorithm development in previous studies. More than 50 different features to address heart rate changes before SCD have been reviewed and general methodology on this area proposed based on variety of studies on ICDs functionality. A comparative study on the prediction performance of these features, using a common database, is also presented. By combining these features with a support vector machine classifier, achieved results have compared well with other studies.
Association Between State Medicaid Eligibility Thresholds and Deaths Due to Substance Use Disorders
Authors: Julia Thornton Snider, Margaret E. Duncan, Mugdha R. Gore, Seth Seabury, Alison R. Silverstein, Mahlet G. Tebeka, Dana P. Goldman
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The United States is currently facing an epidemic of deaths related to substance use disorder (SUD), with totals exceeding those due to motor vehicle crashes and gun violence. The epidemic has led to decreased life expectancy in some populations. In recent years, Medicaid eligibility has expanded in some states, and the association of this expansion with SUD-related deaths is yet to be examined. <h3>Objective</h3> To examine the association between eligibility thresholds for state Medicaid coverage and SUD-related deaths. <h3>Design, Setting, and Participants</h3> Economic evaluation study using a retrospective analysis of state-level data between 2002 and 2015 to determine the association between the Medicaid eligibility threshold and SUD-related deaths, controlling for other relevant policies, state socioeconomic characteristics, fixed effects, and a time trend. Policy variables were lagged by 1 year to allow time for associations to materialize. Data were collected and analyzed from 2016 to 2017. <h3>Exposures</h3> The policy of interest was the state Medicaid eligibility threshold, ie, the highest allowed income that qualifies a person for Medicaid, expressed as a percentage of the federal poverty level. State policies related to mental health, overdose treatment, and law enforcement of drug crimes were included as controls. <h3>Main Outcomes and Measures</h3> The primary outcome was number of SUD-related deaths, obtained from data provided by the Centers for Disease Control and Prevention. <h3>Results</h3> Across 700 state-year observations, the mean (SD) number of SUD-related deaths was 21.15 (6.05) per 100 000 population. Between 2002 and 2015, the national SUD-related death rate increased from 16.0 to 27.5 per 100 000, while the average Medicaid eligibility threshold increased from 87.2% to 97.1% of the federal poverty level. Over this period, every 100–percentage point increase in the Medicaid eligibility threshold (eg, from 50% to 150% of the federal poverty level) was associated with 1.373 (95% CI, −2.732 to −0.014) fewer SUD-related deaths per 100 000 residents, a reduction of 6.50%. In the 22 states with net contractions in eligibility thresholds between 2005 and 2015, an estimated increase of 570 SUD-related deaths (95% CI, −143 to 1283) occurred. In the 28 states that increased eligibility thresholds, an estimated 1045 SUD-related deaths (95% CI, −209 to 2299) may have been prevented. <h3>Conclusions and Relevance</h3> These findings suggest that the overall increase in SUD-related deaths between 2002 and 2015 may have been greater had the average eligibility threshold for Medicaid not increased over this period. Broader eligibility for Medicaid coverage may be one tool to help reduce SUD-related deaths.
French experience of balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension
Authors: Philippe Brenot, Xavier Jaïs, Yu Taniguchi, Carlos Garcia Alonso, Benoit Gerardin, Sacha Mussot, Olaf Mercier, Dominique Fabre, Florence Parent, Mitja Jevnikar, David Montani, Laurent Savale, Olivier Sitbon, Elie Fadel, Marc Humbert, Gérald Simonneau
Journal: European Respiratory Journal (2019)

Aims To evaluate safety and efficacy of balloon pulmonary angioplasty (BPA) in a large cohort of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods From 2014 to 2017, 184 inoperable CTEPH patients underwent 1006 BPA sessions. Safety and efficacy during the first 21 months (initial period) were compared with those of the last 21 months (recent period). A total of 154 patients had a full evaluation after a median duration of 6.1 months. Results Overall, there was a significant improvement in New York Heart Association functional class, 6-min walk distance (mean change +45 m), and a significant decrease in mean pulmonary artery pressure (PAP) and in pulmonary vascular resistance (PVR) by 26% and 43%, respectively. The percentage decreases of mean PAP and PVR were 22% and 37% in the initial period versus 30% and 49% in the recent period, respectively (p&lt;0.05). The main complications included lung injury, which occurred in 9.1% of 1006 sessions (13.3% in the initial period versus 5.9% in the recent period; p&lt;0.001). Per-patient multivariate analysis revealed that baseline mean PAP and the period during which BPA procedure was performed (recent versus initial period) were the strongest factors related to the occurrence of lung injury. 3-year survival was 95.1%. Conclusion This study confirms that a refined BPA strategy improves short-term symptoms, exercise capacity and haemodynamics in inoperable CTEPH patients with an acceptable risk–benefit ratio. Safety and efficacy improve over time, underscoring the unavoidable learning curve for this procedure.
BCMA CAR T cells: the winding path to success
Authors: Ivan Borrello, Philip H. Imus
Journal: Journal of Clinical Investigation (2019)

Chimeric antigen receptor (CAR) T cells have been shown to successfully treat some hematopoietic malignancies. Recognition of a relevant target on malignant cells and the proper costimulatory molecule are essential for CAR T cell efficacy. In this issue of the JCI, Cohen et al. conducted an early phase trial to evaluate B cell maturation antigen–targeting (BCMA-targeting) CAR T cells in patients with refractory multiple myeloma. Patients who received the highest dose of BCMA-targeting CAR T cells in combination with lymphodepletion had the greatest response. The results of the study provide further support for the use of BCMA-targeting CAR T cells for myeloma, and reiterate the importance of space and cell dose for CAR T cell success.
Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction
Authors: Lisa Schmidleithner, Yasser Thabet, Eva Schönfeld, Maren Köhne, Daniel Sommer, Zeinab Abdullah, Timothy Sadlon, Collins Osei-Sarpong, Kotha Subbaramaiah, Francesca Copperi, Kristian Haendler, Tamas Varga, Oliver Schanz, Svenja Bourry, Kevin Bassler, Wolfgang Krebs, Annika E. Peters, Ann-Kathrin Baumgart, Maria Schneeweiss, Kathrin Klee, Susanne V. Schmidt, Simone Nüssing, Jil Sander, Naganari Ohkura, Andreas Waha, Tim Sparwasser, F. Thomas Wunderlich, Irmgard Förster, Thomas Ulas, Heike Weighardt, Shimon Sakaguchi, Alexander Pfeifer, Matthias Blüher, Andrew J. Dannenberg, Nerea Ferreirós, Louis J. Muglia, Claudia Wickenhauser, Simon C. Barry, Joachim L. Schultze, Marc Beyer
Journal: Immunity (2019)
THER-15. FUNCTIONALIZED NANOPARTICLE TRAFFICKING ASSESSED IN A NOVEL MICROFLUIDIC MODEL OF THE BLOOD-BRAIN BARRIER WITH HIGH GRADE GLIOMA SPHEROIDS
Authors: Joelle P Straehla, Cynthia Hajal, Tamara Dacoba, Roger D Kamm, Paula T Hammond
Journal: Neuro-Oncology (2019)

High grade gliomas (HGG) are the most common malignant brain tumor in children, and remain effectively incurable with 5 year overall survival. We developed a library of functionalized nanoparticles (NPs) with ligands targeting BBB shuttle mechanisms. Using the layer-by-layer (LbL) platform to functionally ‘wrap’ polyelectrolytes around a NP core by iterative electrostatic adsorption, we can incorporate a wide range of drugs, modulate release kinetics, and add targeting moieties in a highly tunable system. In this study, we layered a liposomal core with alkyne-modified poly-L-aspartic acid or hyaluronic acid, and functionalized the surface with BBB ligands glutathione (GSH), angiopep-2 (AP2), or transferrin (Tf). Functionalization improved NP uptake in endothelial cells and lowered the IC50 of encapsulated cisplatin in HGG cells over control NPs. To investigate the ability of functionalized NPs to effectively cross the BBB and penetrate tumor cells, we incorporated HGG spheroids into a microfluidic model of co-cultured human astrocytes, pericytes, and induced pluripotent stem cell (iPSC) endothelial cells, which self-assemble into perfusable microvascular networks (µVNs) with properties comparable to the human BBB (Campisi et al. Biomaterials 2018). After perfusing fluorescent LbL NPs into µVNs with and without HGG spheroids, we quantified vascular permeability and found higher overall permeability in spheroid-containing networks. NPs functionalized with AP2 and Tf exhibited higher BBB transit than non-functionalized NPs in networks with and without HGG spheroids. In this work, we establish a new model for testing drug delivery across the BBB and identified promising functionalized drug carriers for HGG. Ongoing studies in murine models are underway to further validate this platform for clinical translation.
Ethical Review and Methodologic Innovation in Phase 1 Cancer Trials
Authors: David C. Norris
Journal: JAMA Pediatrics (2019)

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Chronic hypoxia–induced <i>Cirbp</i> hypermethylation attenuates hypothermic cardioprotection via down-regulation of ubiquinone biosynthesis
Authors: Yiwei Liu, Junyue Xing, Yongnan Li, Qipeng Luo, Zhanhao Su, Xiaoling Zhang, Hao Zhang
Journal: Science Translational Medicine (2019)

Chronic hypoxia–induced hypermethylation attenuates hypothermic cardioprotective effects of Cirbp and ubiquinone biosynthesis in rats and patients.
Neuroinflammation During RNA Viral Infections
Authors: Robyn S. Klein, Charise Garber, Kristen E. Funk, Hamid Salimi, Allison Soung, Marlene Kanmogne, Sindhu Manivasagam, Shannon Agner, Matthew Cain
Journal: Annual Review of Immunology (2019)

Neurotropic RNA viruses continue to emerge and are increasingly linked to diseases of the central nervous system (CNS) despite viral clearance. Indeed, the overall mortality of viral encephalitis in immunocompetent individuals is low, suggesting efficient mechanisms of virologic control within the CNS. Both immune and neural cells participate in this process, which requires extensive innate immune signaling between resident and infiltrating cells, including microglia and monocytes, that regulate the effector functions of antiviral T and B cells as they gain access to CNS compartments. While these interactions promote viral clearance via mainly neuroprotective mechanisms, they may also promote neuropathology and, in some cases, induce persistent alterations in CNS physiology and function that manifest as neurologic and psychiatric diseases. This review discusses mechanisms of RNA virus clearance and neurotoxicity during viral encephalitis with a focus on the cytokines essential for immune and neural cell inflammatory responses and interactions. Understanding neuroimmune communications in the setting of viral infections is essential for the development of treatments that augment neuroprotective processes while limiting ongoing immunopathological processes that cause ongoing CNS disease.
MEDU-30. IDENTIFYING DISTINCTIVE lincRNAs IN THE DIFFERENT MEDULLOBLASTOMA SUBGROUPS
Authors: Shany Freedman, Michal Yalon, Eran Eyal, Nitzan Kol, Marc Remke, Amos Toren, Ruty Mehrian-Shai
Journal: Neuro-Oncology (2019)

INTRODUCTION: Medulloblastoma is the most common malignant pediatric brain tumor. It has been found that medulloblastoma is not a single disease but has distinct molecular subgroups. The current consensus is that there are four core subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 and Group 4.In groups WNT and SHH the mutated pathway is known, wingless and sonic hedgehog respectively however in group 3 and group 4 the mutated pathway is not known. Our aim is to discover lincRNAs that are distinctive in the different medulloblastoma subgroups. Long non coding RNAs (lincRNAs) are functionally defined as transcripts longer than 200 nucleotides in length with no protein coding potential. lincRNA involvement in human cancers etiology is being increasingly proved. METHODS AND RESULTS: We analyzed RNA sequencing of 28 Medulloblastoma samples and quantified the genome wide long non coding RNAs (lincRNA) expression levels. In the current study we report for the first time the medulloblastoma group specific genome wide lincRNAs expression. We identified two lincRNAs that are distinctively highly expressed in group 3 (MB3) and group 4 (MB4). MB3 silencing decreased the migration and invasion abilities of the cells and upon over expression of MB3 these abilities increased suggesting that MB3 has a role in regulating migration and invasion of medulloblastoma tumor cells. MB4 expression was further examined in microarray analysis on a larger cohort of medulloblastoma patient samples and a large cohort (n=1405) of patient samples that include normal brain and different brain tumor samples. MB4 proved to be specific and highly expressed in group 4 Medulloblastoma. CONCLUSIONS: MB3 and MB4 can be a good diagnostic marker, MB3 may be a prognostic marker since group 3 has distinct poor prognosis and in future both may also be a good target for therapy.