tbuckley/cabot-search huggingface dataset:
ACTR-54. PATTERN OF RECURRENCE AND IMPACT ON SURVIVAL OF SALVAGE THERAPIES IN LOW-GRADE GLIOMAS FOLLOWING DOSE-DENSE TEMOZOLOMIDE
Authors: Alessia Pellerino, Roberta Rudà, Andrea Pace, Carmine Carapella Maria, Cristina Dealis, Manuela Caroli, Marina Faedi, Giulia Marchese, Lorenzo Bello, Riccardo Soffietti
Journal: Neuro-Oncology (2018)

INTRODUCTION: Initial chemotherapy with temozolomide (TMZ) may provide some benefit in high-risk low-grade gliomas. No standard treatment is validated at progression. The aim of the study was to investigate which is the optimal salvage therapy after the first progression in terms of PFS and the overall survival (OS). PATIENTS AND We evaluated 49 patients with grade II oligodendroglioma and oligoastrocytoma according to WHO 2007 included in a phase II AINO trial, who progressed following initial chemotherapy alone with TMZ. Molecular data were available in 48 patients: 29 patients were IDH 1/2 mutated, 23 1p/19q codeleted, and 36 MGMT methylated. Median follow up was 140 months. All patients had local tumor progression and patterns on MRI were as follows: a FLAIR lesion in 25 patients (51.0%), a mild patchy enhancing lesion in 14 (28.6%), and a nodular enhancing lesion in the other 10 (20.4%). Twenty-four patients (49%) underwent a second-line chemotherapy, 12 (24.5%) a salvage radiotherapy, 11 (22.4%) a second surgery (10 gross-total resection and 1 subtotal resection), and 2 (4.1%) palliative care. Responses (RANO criteria) following salvage radiotherapy or chemotherapy consisted in PR in 6/38 patients (15.8%), MR in 9/38 (23.7%), SD in 10/38 (26.3%), and PD in 13/38 (34.2%). Median PFS after first salvage therapy was 18 months (IC95% 11–27). Median PFS was 11 months (IC95% 8–74) after radiotherapy, 14 months after chemotherapy and 31 months after surgery (IC95% 18–51, p 0.013). Median OS from the first salvage therapy was 63 months (IC95% 4 - NR). Median OS was 44 months (IC95% 4 NR) after radiotherapy, 38 months (IC95% 22–80) after chemotherapy, and 87 months after surgery (IC95% 11-NR, p 0.09). Reoperation aiming at total or near/total resection seems to offer a probability of a longer PFS and OS compared with the other treatment options.
Variable radiological lung nodule evaluation leads to divergent management recommendations
Authors: Arjun Nair, Emily C. Bartlett, Simon L.F. Walsh, Athol U. Wells, Neal Navani, Georgia Hardavella, Sanjeev Bhalla, Lucio Calandriello, Anand Devaraj, Jin Mo Goo, Jeffrey S. Klein, Heber MacMahon, C.M. Schaefer-Prokop, Joon-Beom Seo, Nicola Sverzellati, Sujal R. Desai
Journal: European Respiratory Journal (2018)

Radiological evaluation of incidentally detected lung nodules on computed tomography (CT) influences management. We assessed international radiological variation in 1) pulmonary nodule characterisation; 2) hypothetical guideline-derived management; and 3) radiologists' management recommendations. 107 radiologists from 25 countries evaluated 69 CT-detected nodules, recording: 1) first-choice composition (solid, part-solid or ground-glass, with percentage confidence); 2) morphological features; 3) dimensions; 4) recommended management; and 5) decision-influencing factors. We modelled hypothetical management decisions on the 2005 and updated 2017 Fleischner Society, and both liberal and parsimonious interpretations of the British Thoracic Society 2015 guidelines. Overall agreement for first-choice nodule composition was good (Fleiss' κ=0.65), but poorest for part-solid nodules (weighted κ 0.62, interquartile range 0.50–0.71). Morphological variables, including spiculation (κ=0.35), showed poor-to-moderate agreement (κ=0.23–0.53). Variation in diameter was greatest at key thresholds (5 mm and 6 mm). Agreement for radiologists' recommendations was poor (κ=0.30); 21% disagreed with the majority. Although agreement within the four guideline-modelled management strategies was good (κ=0.63–0.73), 5–10% of radiologists would disagree with majority decisions if they applied guidelines strictly. Agreement was lowest for part-solid nodules, while significant measurement variation exists at important size thresholds. These variations resulted in generally good agreement for guideline-modelled management, but poor agreement for radiologists' actual recommendations.
Abstract 20134: Transcriptional Profiling Identifies Candidate Regulators of Neonatal Heart Regeneration
Authors: Caitlin O’Meara, Joseph Wamstad, Laurie Boyer, Richard T Lee
Journal: Circulation (2014)

Some higher organisms, such as zebrafish and neonatal mice, are capable of complete and sufficient regeneration of the myocardium following injury, which is thought to occur primarily by proliferation of pre-existing cardiomyocytes. Although adult humans and adult mice lack this cardiac regeneration potential, there is great interest in understanding how regeneration can occur in the heart so that we can activate this process in humans suffering from heart failure. The aim of our study was to identify mechanisms by which mature, post-mitotic adult cardiomyocytes can re-enter the cell cycle to ultimately facilitate heart regeneration following injury. We derived a core transcriptional signature of injury-induced cardiomyocyte regeneration in mouse by comparing global transcriptional programs in a dynamic model of in vitro and in vivo cardiomyocyte differentiation and in an in vitro cardiomyocyte explant model, as well as a neonatal heart resection model. We identified a panel of transcription factors, growth factors, and cytokines, whose expression significantly correlated with the differentiated state of the cell in all datasets examined, suggesting that these factors play a role in regulating cardiomyocyte cell state. Furthermore, potential upstream regulators of core differentially expressed networks were identified using Ingenuity Pathway Analysis and we found that one predicted regulator, interleukin-13 (IL13), significantly induced cardiomyocyte cell cycle activity and STAT6/STAT3 signaling in vitro. siRNA knockdown experiments demonstrated that STAT3/periostin and STAT6 signaling are critical for cardiomyocyte cell cycle activity in response to IL13. These data reveal novel insights into the transcriptional regulation of mammalian heart regeneration and provide the founding circuitry for identifying potential regulators for stimulating cardiomyocyte cell cycle activity.
Audit paints “bleak picture” of diabetes care in England and Wales
Authors: Jonathan Owen
Journal: BMJ (2018)

Around 1.5 million people with diabetes are not getting the care they need, in what health campaigners describe as a “bleak picture” of treatment.

Although a growing number of people with diabetes in England and Wales are being properly cared for, four in 10 are still not getting the care recommended by the UK National Institute for Health and Care Excellence, the latest national diabetes audit has found.1

Patients are supposed to receive at least eight forms of care, including blood tests to measure cardiovascular risk, kidney function, and glucose control and urine tests for kidney disease. They should also be tested for raised blood pressure, checked for signs of foot ulcers, and have their …
Abstract 04: The Most Accurate Massive Transfusion Prediction Score at the Scene of Injury: The Pre-Hospital Traumatic Bleeding Severity Score
Authors: Takayuki Ogura, Keibun Liu, Hiroshi Machida, Kenji Fujizuka, Mitsunobu Nakamura, Minoru Nakano
Journal: Circulation (2018)

Background: Determination of the need for massive transfusion (MT) at the scene of injury is ideal for early activation of a MT protocol. We created and reported The Pre-hospital Traumatic Bleeding Severity Score (ph-TBSS) that is a simple and highly accurate scoring system to predict the need for MT at the scene of injury. However, the comparison study about the predictive value between the ph-TBSS and other MT predictors is not performed. Patients and Methods: A diagnostic comparison study using the registry data of the Gunma Prefectural Helicopter Emergency Medical Service (HEMS) was conducted. Records between Sep. 2012 and Apr. 2017 were reviewed, and adult trauma patients transported by the HEMS were included. A physician in the HEMS is always on board, primary survey including abdominal sonography scanning is performed at the scene of injury, and lactate was measured by portable equipment. The potential predictors of MT (10 units or more of packed red blood cells transfusion within 24 hours of injury) at the scene of injury were defined as following; The ph-TBSS, Assessment of Blood Consumption (ABS) score, the shock index, lactate concentration, and the presence of cold sweat. Each predictor was retrospectively calculated or reviewed from the registry data. Each predictive value was analyzed by the area under the receiver operating characteristic curve (AUROC) and the AUROC comparison analysis was performed. Results: 1025 patients were analyzed. Each AUROC for MT was following; ph-TBSS vs ABC score vs shock index vs lactate concentration vs presence of cold sweat = 0.97 [0.96-0.98] vs 0.83 [0.81-0.85] vs 0.89 [0.87-0.91] vs 0.91 [0.90-0.93] vs 0.70 [0.67-0.72]. The AUROC of the ph-TBSS was significantly higher compared to the AUROC of the other predictors (Bonferroni adjusted p&lt;0.01). Conclusion: At the scene of injury, the ph-TBSS represented the highest predictive value for MT, compared to the ABC score, shock index, lactate concentration, or presence of cold sweat.
Abstract 13521: Novel Protective Role of Cu Transporter ATP7A Against Cardiac Fibrosis by Inhibiting Endothelial-Mesenchymal Transition Mediated Through Snail and Antioxidant-1
Authors: Seock-Won Youn, Sudhahar Varadarajan, Archita Das, Bayasgalan Surenkhuu, Tohru Fukai, Masuko Ushio-Fukai
Journal: Circulation (2015)

Cardiac fibrosis is attributed to excess pathological deposition of extracellular-matrix (ECM) components; however, it is also mediated through endothelial-mesenchymal transition (EndMT) and fibroblast-myofibroblast transition (FMT) with unknown mechanisms. Copper (Cu), essential micronutrient, has been implicated in fibrosis. Bioavailability of Cu is tightly controlled by Cu-transporter ATP7A which obtains Cu from Cu chaperone Antioxidant-1 (Atox1), and delivers Cu to the ECM secretory Cu enzyme lysysl oxidase (LOX) or exclude Cu. Atox1 also functions as a Cu-dependent transcription factor. However, role of ATP7A in cardiac fibrosis remains unknown. Here we show that high dose angiotensin II infusion (740ng/kg/min for 10 days) to ATP7A mutant (ATP7Amut) mice with reduced Cu transport function significantly increased cardiac fibrosis (200%) and Cu (170%) compared to wild type mice. Blood pressure and heart/body weight were similar between each group. ATP7Amut mice showed increased Isolectin B4+/αSMA+ cells, indicating EndMT in fibrosis region, which was associated with increase in fibrosis-related genes (αSMA, TGFβ1/2/3, CTGF). In ATP7Amut fibroblasts, although LOX activity was reduced, phenotypic conversion to αSMA+ myofibroblasts (FMT) was accelerated. In ECs isolated from ATP7Amut mice or ATP7A-depleted HUVECs, EC phenotype was converted to mesenchymal phenotype with reduced expression of ECs markers (VE-cadherin, VEGFR2) and increased mesenchymal markers (αSMA, TGFβ2) and Cu levels. Functionally, conditioned media from ATP7A-depleted HUVECs promoted cardiac fibroblast differentiation to myofibroblasts (FMT). Mechanistically, ATP7A knockdown in ECs increased expression of EndMT master regulatory transcription factor Snail as well as Atox1 (2 fold). Atox1 overexpression by adenovirus increased EndMT-inducing genes (αSMA, TGFβ2, Hey2) via binding to their promoters at Atox1 binding sites (GAAAGA) without affecting EC markers or Snail which is shown to reduce EC markers. In summary, ATP7A limits cardiac fibrosis by inhibiting EndMT and FMT via suppressing transcription factors Snail and Atox1. Thus, ATP7A is a potential therapeutic target for fibrosis-dependent cardiovascular diseases.
Abstract 20954: Abnormal Liver Function Tests Are Association With Adverse Outcomes in Acute Decompensated Heart Failure in the CARRESS Trial
Authors: Jigna Solanki, Kenneth Bilchick, Javelle Wynter, Alex Parker, Hunter Mwansa, Jamie Kennedy, Mohammad Abuannadi, James Bergin, Sula Mazimba
Journal: Circulation (2017)

Introduction: Hepatic congestion with abnormal liver function tests (LFTs), including aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (TBL) complicates acute decompensated heart failure (ADHF). The prognostic implication of abnormal LFTs in ADHF is less studied. Hypothesis: We hypothesized that abnormal LFTs would be associated with unfavorable outcomes in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS) trial. Methods: Cox proportional hazards analysis was performed to assess the association between LFTs (AST, ALT and TBL) at baseline in the CARRESS trial with adverse clinical outcomes, including death, death or HF rehospitalization, and death or any rehospitalization. Correlation analysis was used to assess the relationship between baseline LFTs and BNP, a surrogate of cardiac filling pressures. Results: Among 188 patients (67.9 ± 12.8 years, 25% female), 15.4% died, 35.5% died or had a HF rehospitalization, and 53.8% died or were rehospitalized for any reason. Elevated TBL at baseline was associated with an increased risk of death or rehospitalization for any reason (HR 1.65 per each mg/dL increase in total TBL, 95% CI 1.15-2.38, P=0.007), and a TBL in the upper quartile (&gt; 1.2 mg/dL) was associated with an increased risk of death or HF hospitalization (HR 1.96, 95% CI 1.11-3.45, P=0.02) (Figure). Total bilirubin and BNP at baseline were moderately correlated (r=0.34, P=0.007). There were also no significant associations for AST or ALT with any of the clinical outcomes (P&gt;0.20 for all). Conclusion: Total bilirubin was independently associated with adverse events in ADHF and was also correlated with BNP, a marker of increased cardiac filling pressures. More studies are needed to better define the implications of abnormal LFTs in other HF phenotypes.
IMMU-07. IMMUNE PROFILES IN THE SAN FRANCISCO ADULT GLIOMA STUDY (AGS) USING IMMUNOMETHYLOMICS
Authors: John Wiencke, Annette Molinaro, Gayathri Warrier, Jennifer Clarke, Jennie Taylor, Devin Koestler, Joseph Wiemels, Helen Hansen, Sean Lee, Terri Rice, Lucie McCoy, Lucas Salas, Margaret Wrensch, Brock Christensen, Karl Kelsey
Journal: Neuro-Oncology (2018)

Glioma patients demonstrate abnormalities in peripheral blood leukocytes that have been associated with survival time. Here we assessed immune cell profiles in archival blood samples obtained 5–25 years ago using a novel epigenetic approach called immunomethylomics. We first validated the approach to measure the proportions of CD4 T cells, CD8 T cells, B cells, NK cells, neutrophils, and monocytes in archival blood using the new 850,000 feature EPIC Illumina methylation bead array. The immunomethylomic assay was shown to match the performance of multiparametric flow cytometry and thus is a highly accurate method for immune profiling. We next measured cell profiles in blood from 312 molecularly defined AGS subjects. In this cohort we enriched for patients with triple negative tumor subtypes (IDH wildtype, 1p19q negative, TERT non-mutant). Elevations in the neutrophil lymphocyte ratio (NLR) significantly increased with grade, whereas the proportions of T cells decreased with increasing grade. Using an established cut point of > 4.0 for the NLR revealed that this immune parameter was associated with shorter survival times in glioblastoma (median overall survival (mOS) 12.6 vs. 16.9 months) and non-glioblastoma (mOS 16.7 vs. 36 months) patients. Ongoing analyses of the cohort will be presented to evaluate the effects of age, gender, surgery, chemoradiation and tumor grade on the survival results. Because DNA based immune cell profiles do not require intact cells nor preserved proteins, they provide a powerful tool to glean potentially important immunologic information from historic stored samples that could not otherwise be utilized using current cytometry-based approaches.
Abstract #4280: CXCR4-chemokine receptor and Cannabinoid Receptor 2 (CB2) heterodimerization suggests a mechanism for breast metastasis regulation
Authors: Cimona Hinton, Shalom Avraham, Hava Avraham
Journal: Cancer Research (2009)

G protein-coupled receptors (GPCR) are a large superfamily of transmembrane receptors, regulating diverse functions. G-proteins can function as homo-oligomers or hetero-oligomers; which may modulate signal transduction, signaling desensitization or ligand uncoupling. CXCR4 and CB2 are part of this superfamily of receptors. Chemokine receptors have roles in leukocyte trafficking, and cancer metastasis. CXCR4 is expressed in breast cancer cells, in contrast to normal breast tissues, which do not express CXCR4. Thus, in facilitating metastasis, CXCR4-positive breast cancer cells migrate to organs where its ligand, SDF1\#945;, is highly expressed. Additionally, CXCR4 is linked to developing favorable tumor microenvironments and angiogenesis. Cannabinoid receptors bind to exogenous agonists, and endogenous agonists, termed endocannabinoids. Cannabinoids are involved in cardiovascular activity, inflammation, pain, neuroprotection, tumorigenesis suppression, and more. We observed that breast cancer cells express CB2, and that a CB2 agonist induced heterologous desensitization of CXCR4 in breast cancer cells, through heterodimerization. The CXCR4/CB2 heterodimer was a CXCR4 antagonist; inhibiting SDF1\#945;-mediated migration. Using metastatic human breast cancer cells, receptor expression was confirmed by FACS and immunoprecipitation. Chemotactic assays determined if heterodimerization influenced migratory function. Signaling pathway involvement was determined by western blotting. Both the CXCR4 and CB2 receptors were expressed on the surface of breast cancer cells. Receptor expression was altered when cells were treated with their respective ligands individually, but not simultaneously. When cells were treated with ligands simultaneously, migration of CXCR4 significantly decreased, compared to treatment with SDF1\#945; alone. ERK1/2, not protein kinase B/Akt, appeared to be involved in this phenomenon. GPCR oligomerization and desensitization may suppress signaling cascades associated with individual receptor responses. This is significant since marijuana is deemed useful in the treatment of some cancers, and as a novel target in drug therapy. Although further studies are needed, our model suggests that heterologous desensitization through the CXCR4/CB2 heterodimer may provide novel models of therapy in breast cancer metastasis.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4280.
Abstract 19512: Characterization of Access vs. Non-Access Site Bleeding Following PCI in Patients With Atrial Fibrillation
Authors: Tarek Nafee, Gerald Chi, Megan K Yee, Douglas Arbetter, Duane S Pinto, Roxana Mehran, Cristoph Bode, Jonathan Halperin, Freek W Verheugt, Peter Wildgoose, Paul Burton, Martin van Eickels, Serge Korjian, Yazan Daaboul, Gregory Y Lip, Marc Cohen, Eric D Peterson, Keith A Fox, C. Michael Gibson
Journal: Circulation (2017)

Background: The risk of bleeding is accentuated in patients with atrial fibrillation (AF) who undergo percutaneous coronary interventions (PCI) due to combined anti-platelet/anticoagulant regimens....
INNV-01. PROTECT STUDY: PROPHYLACTIC SKIN TOXICITY THERAPY WITH CLINDAMYCIN AND CLOBETASOL OR SKIN BARRIER IN GLIOBLASTOMA PATIENTS TREATED WITH TUMOR TREATING FIELDS
Authors: Mario Lacouture
Journal: Neuro-Oncology (2018)

Tumor treating fields (TTFields) are non-invasive, anti-mitotic low intensity, intermediate frequency (200 kHz) alternating electric fields. TTFields have demonstrated survival advantage when combined with maintenance TMZ in newly diagnosed glioblastoma. TTFields are applied continuously (>18 hours/day) using a set of four transducer arrays placed on the patients scalp. The main TTFields-related adverse event is mild-moderate dermatitis and pruritus. Strategies that mitigate skin events may improve quality of life, adherence, and prevent treatment interruptions. Several clinical trials are evaluating the concomitant use of TTFields with a variety of immunotherapies which are also associated with dermatologic toxicities. This multicenter, prospective, randomized, double-blind pilot study will test the efficacy and safety of topical clobetasol and clindamycin and a skin barrier to prevent skin events from TTFields. Patients (n=90) will be randomized to receive either: clobetasol propionate, and clindamycin (n=30), topical skin barrier (n=30), or 70% ethanol (n=30, as control group). The primary study outcome is the difference in grade 2 device-related skin toxicity between the arms at study completion (day 90 ± 14 days). The subjects will be assessed (clinical, QoL, interventions) on day 0, 30, 60, at the end of study day 90, grading will be conducted by CTCAE v5.0 and blinded photograph evaluation. A sample size of 90 patients will allow 80% power to detect a 30% difference in grade 2 dermatitis between the treated and non-treated sides with a two-side alpha type I error rate of 5%. Estimated time of accrual is 36 months with an accrual rate of 2–3 patients per month. Anticipated time to complete the study is 39 months.
Abstract P120: Acute Dietary Nitrate Supplementation Does Not Attenuate Oxidative Stress or the Hemodynamic Response During Submaximal Exercise in Hypobaric Hypoxia
Authors: Colin R Carriker, Roger A Vaughan, Christine M Mermier, Trisha A McLain, Kelly E Johnson, Nicholas M Beltz, James J McCormick, Nathan H Cole, Christopher C Witt, Ann L Gibson
Journal: Circulation (2016)

Introduction: Oxidative stress is exacerbated during hypoxic conditions (i.e. high altitude exposure, congestive heart failure, or peripheral artery disease). Dietary nitrate supplementation increases plasma nitrite (denotes nitric oxide bioavailability), reduces resting/submaximal blood pressure (BP) and may enhance exercise performance in certain healthy and diseased populations. Hypothesis: We hypothesized dietary nitrate would improve arterial oxygen saturation (SaO 2 ) and reduce: oxidative stress while reducing submaximal oxygen consumption, BP, and perceived exertion (RPE) during exercise in hypobaric hypoxia (3500m). Methods: Nine well-trained (60.0±7.0 ml/kg/min) males (29±7 yr) completed a maximal aerobic capacity test (VO 2max ) and five 5-min cycling bouts of increasing intensity at their normobaric elevation (1600m). Intensities at 25, 40, 50, 60, 70% VO 2max were used during trial 2 (T2) and trial 3 (T3) cycling bouts. Participants minimized nitrate-rich food consumption during a 4-day dietary washout prior to T2 and T3. Participants consumed a nitrate-depleted placebo (PL) or nitrate-rich (12.8 mmol; NR) beverage 2.5 hours prior to T2 and T3 in a double-blind, placebo-controlled, crossover study. Exercise during hypobaric hypoxia (3500m; T2 and T3) consisted of a 5-min warm-up (25% of normobaric VO 2max ) and four (40, 50, 60, 70% of normobaric VO 2max ) additional 5-min cycling bouts each separated by a 4-min passive rest. Results: Pre-exercise plasma nitrite was elevated following NR consumption compared to PL (p&lt;0.05). Beverage-specific oxygen consumption, SaO 2 , BP and RPE were similar at all submaximal intensities. In both conditions (PL and NR), following exercise at 3500m, markers of oxidative stress (catalase and 8-isoprostane) were elevated compared to baseline resting values (p&lt;0.05). However, post-exercise oxidative stress markers were similar between groups (placebo vs nitrate rich) for both catalase and 8-isoprostane (p=.94 and p=.16; respectively). Conclusions: Our findings do not support the efficacy of dietary nitrate supplementation prior to exercise at altitude in a healthy population.